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1. Age-related deficits in retinal autophagy following intraocular pressure elevation in autophagy reporter mouse model

Author

Afiat, BC, Zhao, D, Wong, VHY, Perera, ND, Turner, BJ, Nguyen, CTO, Bui, BV, Afiat, BC, Zhao, D, Wong, VHY, Perera, ND, Turner, BJ, Nguyen, CTO, and Bui, BV

Abstract

This study quantified age-related changes to retinal autophagy using the CAG-RFP-EGFP-LC3 autophagy reporter mice and considered how aging impacts autophagic responses to acute intraocular pressure (IOP) stress. IOP was elevated to 50 mm Hg for 30 minutes in 3-month-old and 12-month-old CAG-RFP-EGFP-LC3 (n = 7 per age group) and Thy1-YFPh transgenic mice (n = 3 per age group). Compared with younger eyes, older eyes showed diminished basal autophagy in the outer retina, while the inner retina was unaffected. Autophagic flux (red:yellow puncta ratio) was elevated in the inner plexiform layer. Three days following IOP elevation, older eyes showed poorer functional recovery, most notably in ganglion cell responses compared to younger eyes (12 months old: -33.4 ± 5.3% vs. 3 months mice: -13.4 ± 4.5%). This paralleled a reduced capacity to upregulate autophagic puncta volume in the inner retina in older eyes, a response that was seen in younger eyes. Age-related decline in basal and stress-induced autophagy in the retina is associated with greater retinal ganglion cells' susceptibility to IOP elevation.

Published
2023

2. Mapping Motor Neuron Vulnerability in the Neuraxis of Male SOD1G93A Mice Reveals Widespread Loss of Androgen Receptor Occurring Early in Spinal Motor Neurons

Author

McLeod, VM, Chiam, MDF, Perera, ND, Lau, CL, Boon, WC, Turner, BJ, McLeod, VM, Chiam, MDF, Perera, ND, Lau, CL, Boon, WC, and Turner, BJ

Abstract

Sex steroid hormones have been implicated as disease modifiers in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Androgens, signalling via the androgen receptor (AR), predominate in males, and have widespread actions in the periphery and the central nervous system (CNS). AR translocates to the cell nucleus when activated upon binding androgens, whereby it regulates transcription of target genes via the classical genomic signalling pathway. We previously reported that AR protein is decreased in the lumbar spinal cord tissue of symptomatic male SOD1G93A mice. Here, we further explored the changes in AR within motor neurons (MN) of the CNS, assessing their nuclear AR content and propensity to degenerate by endstage disease in male SOD1G93A mice. We observed that almost all motor neuron populations had undergone significant loss in nuclear AR in SOD1G93A mice. Interestingly, loss of nuclear AR was evident in lumbar spinal MNs as early as the pre-symptomatic age of 60 days. Several MN populations with high AR content were identified which did not degenerate in SOD1G93A mice. These included the brainstem ambiguus and vagus nuclei, and the sexually dimorphic spinal MNs: cremaster, dorsolateral nucleus (DLN) and spinal nucleus of bulbocavernosus (SNB). In conclusion, we demonstrate that AR loss directly associates with MN vulnerability and disease progression in the SOD1G93A mouse model of ALS.

Published
2022

3. The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

Author

Teyssou, E, Chartier, L, Roussel, D, Perera, ND, Nemazanyy, I, Langui, D, Albert, M, Larmonier, T, Saker, S, Salachas, F, Pradat, P-F, Meininger, V, Ravassard, P, Cote, F, Lobsiger, CS, Boillee, S, Turner, BJ, Seilhean, D, Millecamps, S, Teyssou, E, Chartier, L, Roussel, D, Perera, ND, Nemazanyy, I, Langui, D, Albert, M, Larmonier, T, Saker, S, Salachas, F, Pradat, P-F, Meininger, V, Ravassard, P, Cote, F, Lobsiger, CS, Boillee, S, Turner, BJ, Seilhean, D, and Millecamps, S

Abstract

Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.

Published
2022

4. Metabolic Dysfunction in Motor Neuron Disease: Shedding Light through the Lens of Autophagy

Author

De Silva, S, Turner, BJ, Perera, ND, De Silva, S, Turner, BJ, and Perera, ND

Abstract

Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.

Published
2022

5. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Author

Klionsky, DJ, Abdel-Aziz, AK, Abdelfatah, S, Abdellatif, M, Abdoli, A, Abel, S, Abeliovich, H, Abildgaard, MH, Abudu, YP, Acevedo-Arozena, A, Adamopoulos, IE, Adeli, K, Adolph, TE, Adornetto, A, Aflaki, E, Agam, G, Agarwal, A, Aggarwal, BB, Agnello, M, Agostinis, P, Agrewala, JN, Agrotis, A, Aguilar, PV, Ahmad, ST, Ahmed, ZM, Ahumada-Castro, U, Aits, S, Aizawa, S, Akkoc, Y, Akoumianaki, T, Akpinar, HA, Al-Abd, AM, Al-Akra, L, Al-Gharaibeh, A, Alaoui-Jamali, MA, Alberti, S, Alcocer-Gómez, E, Alessandri, C, Ali, M, Alim Al-Bari, MA, Aliwaini, S, Alizadeh, J, Almacellas, E, Almasan, A, Alonso, A, Alonso, GD, Altan-Bonnet, N, Altieri, DC, Álvarez, ÉMC, Alves, S, Alves da Costa, C, Alzaharna, MM, Amadio, M, Amantini, C, Amaral, C, Ambrosio, S, Amer, AO, Ammanathan, V, An, Z, Andersen, SU, Andrabi, SA, Andrade-Silva, M, Andres, AM, Angelini, S, Ann, D, Anozie, UC, Ansari, MY, Antas, P, Antebi, A, Antón, Z, Anwar, T, Apetoh, L, Apostolova, N, Araki, T, Araki, Y, Arasaki, K, Araújo, WL, Araya, J, Arden, C, Arévalo, M-A, Arguelles, S, Arias, E, Arikkath, J, Arimoto, H, Ariosa, AR, Armstrong-James, D, Arnauné-Pelloquin, L, Aroca, A, Arroyo, DS, Arsov, I, Artero, R, Asaro, DML, Aschner, M, Ashrafizadeh, M, Ashur-Fabian, O, Atanasov, AG, Au, AK, Auberger, P, Auner, HW, Aurelian, L, Autelli, R, Avagliano, L, Ávalos, Y, Aveic, S, Aveleira, CA, Avin-Wittenberg, T, Aydin, Y, Ayton, S, Ayyadevara, S, Azzopardi, M, Baba, M, Backer, JM, Backues, SK, Bae, D-H, Bae, O-N, Bae, SH, Baehrecke, EH, Baek, A, Baek, S-H, Baek, SH, Bagetta, G, Bagniewska-Zadworna, A, Bai, H, Bai, J, Bai, X, Bai, Y, Bairagi, N, Baksi, S, Balbi, T, Baldari, CT, Balduini, W, Ballabio, A, Ballester, M, Balazadeh, S, Balzan, R, Bandopadhyay, R, Banerjee, S, Bánréti, Á, Bao, Y, Baptista, MS, Baracca, A, Barbati, C, Bargiela, A, Barilà, D, Barlow, PG, Barmada, SJ, Barreiro, E, Barreto, GE, Bartek, J, Bartel, B, Bartolome, A, Barve, GR, Basagoudanavar, SH, Bassham, DC, Bast, RC, Basu, A, Batoko, H, Batten, I, Baulieu, EE, Baumgarner, BL, Bayry, J, Beale, R, Beau, I, Beaumatin, F, Bechara, LRG, Beck, GR, Beers, MF, Begun, J, Behrends, C, Behrens, GMN, Bei, R, Bejarano, E, Bel, S, Behl, C, Belaid, A, Belgareh-Touzé, N, Bellarosa, C, Belleudi, F, Belló Pérez, M, Bello-Morales, R, Beltran, JSDO, Beltran, S, Benbrook, DM, Bendorius, M, Benitez, BA, Benito-Cuesta, I, Bensalem, J, Berchtold, MW, Berezowska, S, Bergamaschi, D, Bergami, M, Bergmann, A, Berliocchi, L, Berlioz-Torrent, C, Bernard, A, Berthoux, L, Besirli, CG, Besteiro, S, Betin, VM, Beyaert, R, Bezbradica, JS, Bhaskar, K, Bhatia-Kissova, I, Bhattacharya, R, Bhattacharya, S, Bhattacharyya, S, Bhuiyan, MS, Bhutia, SK, Bi, L, Bi, X, Biden, TJ, Bijian, K, Billes, VA, Binart, N, Bincoletto, C, Birgisdottir, AB, Bjorkoy, G, Blanco, G, Blas-Garcia, A, Blasiak, J, Blomgran, R, Blomgren, K, Blum, JS, Boada-Romero, E, Boban, M, Boesze-Battaglia, K, Boeuf, P, Boland, B, Bomont, P, Bonaldo, P, Bonam, SR, Bonfili, L, Bonifacino, JS, Boone, BA, Bootman, MD, Bordi, M, Borner, C, Bornhauser, BC, Borthakur, G, Bosch, J, Bose, S, Botana, LM, Botas, J, Boulanger, CM, Boulton, ME, Bourdenx, M, Bourgeois, B, Bourke, NM, Bousquet, G, Boya, P, Bozhkov, PV, Bozi, LHM, Bozkurt, TO, Brackney, DE, Brandts, CH, Braun, RJ, Braus, GH, Bravo-Sagua, R, Bravo-San Pedro, JM, Brest, P, Bringer, M-A, Briones-Herrera, A, Broaddus, VC, Brodersen, P, Brodsky, JL, Brody, SL, Bronson, PG, Bronstein, JM, Brown, CN, Brown, RE, Brum, PC, Brumell, JH, Brunetti-Pierri, N, Bruno, D, Bryson-Richardson, RJ, Bucci, C, Buchrieser, C, Bueno, M, Buitrago-Molina, LE, Buraschi, S, Buch, S, Buchan, JR, Buckingham, EM, Budak, H, Budini, M, Bultynck, G, Burada, F, Burgoyne, JR, Burón, MI, Bustos, V, Büttner, S, Butturini, E, Byrd, A, Cabas, I, Cabrera-Benitez, S, Cadwell, K, Cai, J, Cai, L, Cai, Q, Cairó, M, Calbet, JA, Caldwell, GA, Caldwell, KA, Call, JA, Calvani, R, Calvo, AC, Calvo-Rubio Barrera, M, Camara, NO, Camonis, JH, Camougrand, N, Campanella, M, Campbell, EM, Campbell-Valois, F-X, Campello, S, Campesi, I, Campos, JC, Camuzard, O, Cancino, J, Candido de Almeida, D, Canesi, L, Caniggia, I, Canonico, B, Cantí, C, Cao, B, Caraglia, M, Caramés, B, Carchman, EH, Cardenal-Muñoz, E, Cardenas, C, Cardenas, L, Cardoso, SM, Carew, JS, Carle, GF, Carleton, G, Carloni, S, Carmona-Gutierrez, D, Carneiro, LA, Carnevali, O, Carosi, JM, Carra, S, Carrier, A, Carrier, L, Carroll, B, Carter, AB, Carvalho, AN, Casanova, M, Casas, C, Casas, J, Cassioli, C, Castillo, EF, Castillo, K, Castillo-Lluva, S, Castoldi, F, Castori, M, Castro, AF, Castro-Caldas, M, Castro-Hernandez, J, Castro-Obregon, S, Catz, SD, Cavadas, C, Cavaliere, F, Cavallini, G, Cavinato, M, Cayuela, ML, Cebollada Rica, P, Cecarini, V, Cecconi, F, Cechowska-Pasko, M, Cenci, S, Ceperuelo-Mallafré, V, Cerqueira, JJ, Cerutti, JM, Cervia, D, Cetintas, VB, Cetrullo, S, Chae, H-J, Chagin, AS, Chai, C-Y, Chakrabarti, G, Chakrabarti, O, Chakraborty, T, Chami, M, Chamilos, G, Chan, DW, Chan, EYW, Chan, ED, Chan, HYE, Chan, HH, Chan, H, Chan, MTV, Chan, YS, Chandra, PK, Chang, C-P, Chang, C, Chang, H-C, Chang, K, Chao, J, Chapman, T, Charlet-Berguerand, N, Chatterjee, S, Chaube, SK, Chaudhary, A, Chauhan, S, Chaum, E, Checler, F, Cheetham, ME, Chen, C-S, Chen, G-C, Chen, J-F, Chen, LL, Chen, L, Chen, M, Chen, M-K, Chen, N, Chen, Q, Chen, R-H, Chen, S, Chen, W, Chen, X-M, Chen, X-W, Chen, X, Chen, Y, Chen, Y-G, Chen, Y-J, Chen, Y-Q, Chen, ZS, Chen, Z, Chen, Z-H, Chen, ZJ, Cheng, H, Cheng, J, Cheng, S-Y, Cheng, W, Cheng, X, Cheng, X-T, Cheng, Y, Cheng, Z, Cheong, H, Cheong, JK, Chernyak, BV, Cherry, S, Cheung, CFR, Cheung, CHA, Cheung, K-H, Chevet, E, Chi, RJ, Chiang, AKS, Chiaradonna, F, Chiarelli, R, Chiariello, M, Chica, N, Chiocca, S, Chiong, M, Chiou, S-H, Chiramel, AI, Chiurchiù, V, Cho, D-H, Choe, S-K, Choi, AMK, Choi, ME, Choudhury, KR, Chow, NS, Chu, CT, Chua, JP, Chua, JJE, Chung, H, Chung, KP, Chung, S, Chung, S-H, Chung, Y-L, Cianfanelli, V, Ciechomska, IA, Cifuentes, M, Cinque, L, Cirak, S, Cirone, M, Clague, MJ, Clarke, R, Clementi, E, Coccia, EM, Codogno, P, Cohen, E, Cohen, MM, Colasanti, T, Colasuonno, F, Colbert, RA, Colell, A, Čolić, M, Coll, NS, Collins, MO, Colombo, MI, Colón-Ramos, DA, Combaret, L, Comincini, S, Cominetti, MR, Consiglio, A, Conte, A, Conti, F, Contu, VR, Cookson, MR, Coombs, KM, Coppens, I, Corasaniti, MT, Corkery, DP, Cordes, N, Cortese, K, Costa, MDC, Costantino, S, Costelli, P, Coto-Montes, A, Crack, PJ, Crespo, JL, Criollo, A, Crippa, V, Cristofani, R, Csizmadia, T, Cuadrado, A, Cui, B, Cui, J, Cui, Y, Culetto, E, Cumino, AC, Cybulsky, AV, Czaja, MJ, Czuczwar, SJ, D'Adamo, S, D'Amelio, M, D'Arcangelo, D, D'Lugos, AC, D'Orazi, G, da Silva, JA, Dafsari, HS, Dagda, RK, Dagdas, Y, Daglia, M, Dai, X, Dai, Y, Dal Col, J, Dalhaimer, P, Dalla Valle, L, Dallenga, T, Dalmasso, G, Damme, M, Dando, I, Dantuma, NP, Darling, AL, Das, H, Dasarathy, S, Dasari, SK, Dash, S, Daumke, O, Dauphinee, AN, Davies, JS, Dávila, VA, Davis, RJ, Davis, T, Dayalan Naidu, S, De Amicis, F, De Bosscher, K, De Felice, F, De Franceschi, L, De Leonibus, C, de Mattos Barbosa, MG, De Meyer, GRY, De Milito, A, De Nunzio, C, De Palma, C, De Santi, M, De Virgilio, C, De Zio, D, Debnath, J, DeBosch, BJ, Decuypere, J-P, Deehan, MA, Deflorian, G, DeGregori, J, Dehay, B, Del Rio, G, Delaney, JR, Delbridge, LMD, Delorme-Axford, E, Delpino, MV, Demarchi, F, Dembitz, V, Demers, ND, Deng, H, Deng, Z, Dengjel, J, Dent, P, Denton, D, DePamphilis, ML, Der, CJ, Deretic, V, Descoteaux, A, Devis, L, Devkota, S, Devuyst, O, Dewson, G, Dharmasivam, M, Dhiman, R, di Bernardo, D, Di Cristina, M, Di Domenico, F, Di Fazio, P, Di Fonzo, A, Di Guardo, G, Di Guglielmo, GM, Di Leo, L, Di Malta, C, Di Nardo, A, Di Rienzo, M, Di Sano, F, Diallinas, G, Diao, J, Diaz-Araya, G, Díaz-Laviada, I, Dickinson, JM, Diederich, M, Dieudé, M, Dikic, I, Ding, S, Ding, W-X, Dini, L, Dinić, J, Dinic, M, Dinkova-Kostova, AT, Dionne, MS, Distler, JHW, Diwan, A, Dixon, IMC, Djavaheri-Mergny, M, Dobrinski, I, Dobrovinskaya, O, Dobrowolski, R, Dobson, RCJ, Đokić, J, Dokmeci Emre, S, Donadelli, M, Dong, B, Dong, X, Dong, Z, Dorn Ii, GW, Dotsch, V, Dou, H, Dou, J, Dowaidar, M, Dridi, S, Drucker, L, Du, A, Du, C, Du, G, Du, H-N, Du, L-L, du Toit, A, Duan, S-B, Duan, X, Duarte, SP, Dubrovska, A, Dunlop, EA, Dupont, N, Durán, RV, Dwarakanath, BS, Dyshlovoy, SA, Ebrahimi-Fakhari, D, Eckhart, L, Edelstein, CL, Efferth, T, Eftekharpour, E, Eichinger, L, Eid, N, Eisenberg, T, Eissa, NT, Eissa, S, Ejarque, M, El Andaloussi, A, El-Hage, N, El-Naggar, S, Eleuteri, AM, El-Shafey, ES, Elgendy, M, Eliopoulos, AG, Elizalde, MM, Elks, PM, Elsasser, H-P, Elsherbiny, ES, Emerling, BM, Emre, NCT, Eng, CH, Engedal, N, Engelbrecht, A-M, Engelsen, AST, Enserink, JM, Escalante, R, Esclatine, A, Escobar-Henriques, M, Eskelinen, E-L, Espert, L, Eusebio, M-O, Fabrias, G, Fabrizi, C, Facchiano, A, Facchiano, F, Fadeel, B, Fader, C, Faesen, AC, Fairlie, WD, Falcó, A, Falkenburger, BH, Fan, D, Fan, J, Fan, Y, Fang, EF, Fang, Y, Fanto, M, Farfel-Becker, T, Faure, M, Fazeli, G, Fedele, AO, Feldman, AM, Feng, D, Feng, J, Feng, L, Feng, Y, Feng, W, Fenz Araujo, T, Ferguson, TA, Fernández, ÁF, Fernandez-Checa, JC, Fernández-Veledo, S, Fernie, AR, Ferrante, AW, Ferraresi, A, Ferrari, MF, Ferreira, JCB, Ferro-Novick, S, Figueras, A, Filadi, R, Filigheddu, N, Filippi-Chiela, E, Filomeni, G, Fimia, GM, Fineschi, V, Finetti, F, Finkbeiner, S, Fisher, EA, Fisher, PB, Flamigni, F, Fliesler, SJ, Flo, TH, Florance, I, Florey, O, Florio, T, Fodor, E, Follo, C, Fon, EA, Forlino, A, Fornai, F, Fortini, P, Fracassi, A, Fraldi, A, Franco, B, Franco, R, Franconi, F, Frankel, LB, Friedman, SL, Fröhlich, LF, Frühbeck, G, Fuentes, JM, Fujiki, Y, Fujita, N, Fujiwara, Y, Fukuda, M, Fulda, S, Furic, L, Furuya, N, Fusco, C, Gack, MU, Gaffke, L, Galadari, S, Galasso, A, Galindo, MF, Gallolu Kankanamalage, S, Galluzzi, L, Galy, V, Gammoh, N, Gan, B, Ganley, IG, Gao, F, Gao, H, Gao, M, Gao, P, Gao, S-J, Gao, W, Gao, X, Garcera, A, Garcia, MN, Garcia, VE, García-Del Portillo, F, Garcia-Escudero, V, Garcia-Garcia, A, Garcia-Macia, M, García-Moreno, D, Garcia-Ruiz, C, García-Sanz, P, Garg, AD, Gargini, R, Garofalo, T, Garry, RF, Gassen, NC, Gatica, D, Ge, L, Ge, W, Geiss-Friedlander, R, Gelfi, C, Genschik, P, Gentle, IE, Gerbino, V, Gerhardt, C, Germain, K, Germain, M, Gewirtz, DA, Ghasemipour Afshar, E, Ghavami, S, Ghigo, A, Ghosh, M, Giamas, G, Giampietri, C, Giatromanolaki, A, Gibson, GE, Gibson, SB, Ginet, V, Giniger, E, Giorgi, C, Girao, H, Girardin, SE, Giridharan, M, Giuliano, S, Giulivi, C, Giuriato, S, Giustiniani, J, Gluschko, A, Goder, V, Goginashvili, A, Golab, J, Goldstone, DC, Golebiewska, A, Gomes, LR, Gomez, R, Gómez-Sánchez, R, Gomez-Puerto, MC, Gomez-Sintes, R, Gong, Q, Goni, FM, González-Gallego, J, Gonzalez-Hernandez, T, Gonzalez-Polo, RA, Gonzalez-Reyes, JA, González-Rodríguez, P, Goping, IS, Gorbatyuk, MS, Gorbunov, NV, Görgülü, K, Gorojod, RM, Gorski, SM, 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T, Soleimanpour, SA, Soler, RM, Solovchenko, A, Somarelli, JA, Sonawane, A, Song, F, Song, HK, Song, J-X, Song, K, Song, Z, Soria, LR, Sorice, M, Soukas, AA, Soukup, S-F, Sousa, D, Sousa, N, Spagnuolo, PA, Spector, SA, Srinivas Bharath, MM, St Clair, D, Stagni, V, Staiano, L, Stalnecker, CA, Stankov, MV, Stathopulos, PB, Stefan, K, Stefan, SM, Stefanis, L, Steffan, JS, Steinkasserer, A, Stenmark, H, Sterneckert, J, Stevens, C, Stoka, V, Storch, S, Stork, B, Strappazzon, F, Strohecker, AM, Stupack, DG, Su, H, Su, L-Y, Su, L, Suarez-Fontes, AM, Subauste, CS, Subbian, S, Subirada, PV, Sudhandiran, G, Sue, CM, Sui, X, Summers, C, Sun, G, Sun, J, Sun, K, Sun, M-X, Sun, Q, Sun, Y, Sun, Z, Sunahara, KKS, Sundberg, E, Susztak, K, Sutovsky, P, Suzuki, H, Sweeney, G, Symons, JD, Sze, SCW, Szewczyk, NJ, Tabęcka-Łonczynska, A, Tabolacci, C, Tacke, F, Taegtmeyer, H, Tafani, M, Tagaya, M, Tai, H, Tait, SWG, Takahashi, Y, Takats, S, Talwar, P, Tam, C, Tam, SY, Tampellini, D, Tamura, A, Tan, CT, Tan, E-K, Tan, Y-Q, Tanaka, M, Tang, D, Tang, J, Tang, T-S, Tanida, I, Tao, Z, Taouis, M, Tatenhorst, L, Tavernarakis, N, Taylor, A, Taylor, GA, Taylor, JM, Tchetina, E, Tee, AR, Tegeder, I, Teis, D, Teixeira, N, Teixeira-Clerc, F, Tekirdag, KA, Tencomnao, T, Tenreiro, S, Tepikin, AV, Testillano, PS, Tettamanti, G, Tharaux, P-L, Thedieck, K, Thekkinghat, AA, Thellung, S, Thinwa, JW, Thirumalaikumar, VP, Thomas, SM, Thomes, PG, Thorburn, A, Thukral, L, Thum, T, Thumm, M, Tian, L, Tichy, A, Till, A, Timmerman, V, Titorenko, VI, Todi, SV, Todorova, K, Toivonen, JM, Tomaipitinca, L, Tomar, D, Tomas-Zapico, C, Tomić, S, Tong, BC-K, Tong, C, Tong, X, Tooze, SA, Torgersen, ML, Torii, S, Torres-López, L, Torriglia, A, Towers, CG, Towns, R, Toyokuni, S, Trajkovic, V, Tramontano, D, Tran, Q-G, Travassos, LH, Trelford, CB, Tremel, S, Trougakos, IP, Tsao, BP, Tschan, MP, Tse, H-F, Tse, TF, Tsugawa, H, Tsvetkov, AS, Tumbarello, DA, Tumtas, Y, Tuñón, MJ, Turcotte, S, Turk, B, Turk, V, Turner, BJ, Tuxworth, RI, Tyler, JK, Tyutereva, EV, Uchiyama, Y, Ugun-Klusek, A, Uhlig, HH, Ułamek-Kozioł, M, Ulasov, IV, Umekawa, M, Ungermann, C, Unno, R, Urbe, S, Uribe-Carretero, E, Üstün, S, Uversky, VN, Vaccari, T, Vaccaro, MI, Vahsen, BF, Vakifahmetoglu-Norberg, H, Valdor, R, Valente, MJ, Valko, A, Vallee, RB, Valverde, AM, Van den Berghe, G, van der Veen, S, Van Kaer, L, van Loosdregt, J, van Wijk, SJL, Vandenberghe, W, Vanhorebeek, I, Vannier-Santos, MA, Vannini, N, Vanrell, MC, Vantaggiato, C, Varano, G, Varela-Nieto, I, Varga, M, Vasconcelos, MH, Vats, S, Vavvas, DG, Vega-Naredo, I, Vega-Rubin-de-Celis, S, Velasco, G, Velázquez, AP, Vellai, T, Vellenga, E, Velotti, F, Verdier, M, Verginis, P, Vergne, I, Verkade, P, Verma, M, Verstreken, P, Vervliet, T, Vervoorts, J, Vessoni, AT, Victor, VM, Vidal, M, Vidoni, C, Vieira, OV, Vierstra, RD, Viganó, S, Vihinen, H, Vijayan, V, Vila, M, Vilar, M, Villalba, JM, Villalobo, A, Villarejo-Zori, B, Villarroya, F, Villarroya, J, Vincent, O, Vindis, C, Viret, C, Viscomi, MT, Visnjic, D, Vitale, I, Vocadlo, DJ, Voitsekhovskaja, OV, Volonté, C, Volta, M, Vomero, M, Von Haefen, C, Vooijs, MA, Voos, W, Vucicevic, L, Wade-Martins, R, Waguri, S, Waite, KA, Wakatsuki, S, Walker, DW, Walker, MJ, Walker, SA, Walter, J, Wandosell, FG, Wang, B, Wang, C-Y, Wang, C, Wang, D, Wang, F, Wang, G, Wang, H, Wang, H-G, Wang, J, Wang, K, Wang, L, Wang, MH, Wang, M, Wang, N, Wang, P, Wang, QJ, Wang, Q, Wang, QK, Wang, QA, Wang, W-T, Wang, W, Wang, X, Wang, Y, Wang, Y-Y, Wang, Z, Warnes, G, Warnsmann, V, Watada, H, Watanabe, E, Watchon, M, Wawrzyńska, A, Weaver, TE, Wegrzyn, G, Wehman, AM, Wei, H, Wei, L, Wei, T, Wei, Y, Weiergräber, OH, Weihl, CC, Weindl, G, Weiskirchen, R, Wells, A, Wen, RH, Wen, X, Werner, A, Weykopf, B, Wheatley, SP, Whitton, JL, Whitworth, AJ, Wiktorska, K, Wildenberg, ME, Wileman, T, Wilkinson, S, Willbold, D, Williams, B, Williams, RSB, Williams, RL, Williamson, PR, Wilson, RA, Winner, B, Winsor, NJ, Witkin, SS, Wodrich, H, Woehlbier, U, Wollert, T, Wong, E, Wong, JH, Wong, RW, Wong, VKW, Wong, WW-L, Wu, A-G, Wu, C, Wu, J, Wu, KK, Wu, M, Wu, S-Y, Wu, S, Wu, WKK, Wu, X, Wu, Y-W, Wu, Y, Xavier, RJ, Xia, H, Xia, L, Xia, Z, Xiang, G, Xiang, J, Xiang, M, Xiang, W, Xiao, B, Xiao, G, Xiao, H, Xiao, H-T, Xiao, J, Xiao, L, Xiao, S, Xiao, Y, Xie, B, Xie, C-M, Xie, M, Xie, Y, Xie, Z, Xilouri, M, Xu, C, Xu, E, Xu, H, Xu, J, Xu, L, Xu, WW, Xu, X, Xue, Y, Yakhine-Diop, SMS, Yamaguchi, M, Yamaguchi, O, Yamamoto, A, Yamashina, S, Yan, S, Yan, S-J, Yan, Z, Yanagi, Y, Yang, C, Yang, D-S, Yang, H, Yang, H-T, Yang, J-M, Yang, J, Yang, L, Yang, M, Yang, P-M, Yang, Q, Yang, S, Yang, S-F, Yang, W, Yang, WY, Yang, X, Yang, Y, Yao, H, Yao, S, Yao, X, Yao, Y-G, Yao, Y-M, Yasui, T, Yazdankhah, M, Yen, PM, Yi, C, Yin, X-M, Yin, Y, Yin, Z, Ying, M, Ying, Z, Yip, CK, Yiu, SPT, Yoo, YH, Yoshida, K, Yoshii, SR, Yoshimori, T, Yousefi, B, Yu, B, Yu, H, Yu, J, Yu, L, Yu, M-L, Yu, S-W, Yu, VC, Yu, WH, Yu, Z, Yuan, J, Yuan, L-Q, Yuan, S, Yuan, S-SF, Yuan, Y, Yuan, Z, Yue, J, Yue, Z, Yun, J, Yung, RL, Zacks, DN, Zaffagnini, G, Zambelli, VO, Zanella, I, Zang, QS, Zanivan, S, Zappavigna, S, Zaragoza, P, Zarbalis, KS, Zarebkohan, A, Zarrouk, A, Zeitlin, SO, Zeng, J, Zeng, J-D, Žerovnik, E, Zhan, L, Zhang, B, Zhang, DD, Zhang, H, Zhang, H-L, Zhang, J, Zhang, J-P, Zhang, KYB, Zhang, LW, Zhang, L, Zhang, M, Zhang, P, Zhang, S, Zhang, W, Zhang, X, Zhang, X-W, Zhang, XD, Zhang, Y, Zhang, Y-D, Zhang, Y-Y, Zhang, Z, Zhao, H, Zhao, L, Zhao, S, Zhao, T, Zhao, X-F, Zhao, Y, Zheng, G, Zheng, K, Zheng, L, Zheng, S, Zheng, X-L, Zheng, Y, Zheng, Z-G, Zhivotovsky, B, Zhong, Q, Zhou, A, Zhou, B, Zhou, C, Zhou, G, Zhou, H, Zhou, J, Zhou, K, Zhou, R, Zhou, X-J, Zhou, Y, Zhou, Z-Y, Zhou, Z, Zhu, B, Zhu, C, Zhu, G-Q, Zhu, H, Zhu, W-G, Zhu, Y, Zhuang, H, Zhuang, X, Zientara-Rytter, K, Zimmermann, CM, Ziviani, E, Zoladek, T, Zong, W-X, Zorov, DB, Zorzano, A, Zou, W, Zou, Z, Zuryn, S, Zwerschke, W, Brand-Saberi, B, Dong, XC, Kenchappa, CS, Lin, Y, Oshima, S, Rong, Y, Sluimer, JC, Stallings, CL, and Tong, C-K

Abstract

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Published
2021

6. Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice

Author

Perera, ND, Tomas, D, Wanniarachchillage, N, Cuic, B, Luikinga, SJ, Rytova, V, Turner, BJ, Perera, ND, Tomas, D, Wanniarachchillage, N, Cuic, B, Luikinga, SJ, Rytova, V, and Turner, BJ

Abstract

Autophagy, which mediates the delivery of cytoplasmic substrates to the lysosome for degradation, is essential for maintaining proper cell homeostasis in physiology, ageing, and disease. There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. Here, we demonstrate autophagy impairment in spinal cords of mice expressing mutant TDP-43Q331K or co-expressing TDP-43WTxQ331K transgenes. The clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy. Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice, shown by truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance. Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons. These findings also emphasise the importance of balancing autophagy stimulation with the potential negative consequences of hyperactive mitophagy in ALS and other neurodegenerative diseases.

Published
2021

7. Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting

Author

Amin, A, Perera, ND, Beart, PM, Turner, BJ, Shabanpoor, F, Amin, A, Perera, ND, Beart, PM, Turner, BJ, and Shabanpoor, F

Abstract

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular "clearance" system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.

Published
2020

8. Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression

Author

Perera, ND, Sheean, RK, Lau, CL, Shin, YS, Beart, PM, Horne, MK, Turner, BJ, Perera, ND, Sheean, RK, Lau, CL, Shin, YS, Beart, PM, Horne, MK, and Turner, BJ

Abstract

Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.

Published
2018

9. Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students

Author

Lepeta, K, Lourenco, MV, Schweitzer, BC, Martino Adami, PV, Banerjee, P, Catuara-Solarz, S, Revenga, MDLF, Marc Guillem, A, Haidar, M, Ijomone, OM, Nadorp, B, Qi, L, Perera, ND, Refsgaard, LK, Reid, KM, Sabbar, M, Sahoo, A, Schaefer, N, Sheean, RK, Suska, A, Verma, R, Vicidomini, C, Wright, D, Zhang, X-D, Seidenbecher, C, Lepeta, K, Lourenco, MV, Schweitzer, BC, Martino Adami, PV, Banerjee, P, Catuara-Solarz, S, Revenga, MDLF, Marc Guillem, A, Haidar, M, Ijomone, OM, Nadorp, B, Qi, L, Perera, ND, Refsgaard, LK, Reid, KM, Sabbar, M, Sahoo, A, Schaefer, N, Sheean, RK, Suska, A, Verma, R, Vicidomini, C, Wright, D, Zhang, X-D, and Seidenbecher, C

Abstract

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

Published
2016

10. Effect of thymic stimulation of CD4+T cell expansion on disease onset and progression in mutant SOD1 mice

Author

Sheean, RK, Weston, RH, Perera, ND, D'Amico, A, Nutt, SL, Turner, BJ, Sheean, RK, Weston, RH, Perera, ND, D'Amico, A, Nutt, SL, and Turner, BJ

Abstract

BACKGROUND: The peripheral immune system is implicated in modulating microglial activation, neurodegeneration and disease progression in amyotrophic lateral sclerosis (ALS). Specifically, there is reduced thymic function and regulatory T cell (Treg) number in ALS patients and mutant superoxide dismutase 1 (SOD1) mice, while passive transfer of Tregs ameliorates disease in mutant SOD1 mice. Here, we assessed the effects of augmenting endogenous CD4+ T cell number by stimulating the thymus using surgical castration on the phenotype of transgenic SOD1(G93A) mice. METHOD: Male SOD1(G93A) mice were castrated or sham operated, and weight loss, disease onset and progression were examined. Thymus atrophy and blood CD4+, CD8+ and CD4+ FoxP3+ T cell numbers were determined by fluorescence activated cell sorting (FACS). Motor neuron counts, glial cell activation and androgen receptor (AR) expression in the spinal cord were investigated using immunohistochemistry and Western blotting. Differences between castrated and sham mice were analysed using an unpaired t test or one-way ANOVA. RESULTS: Castration significantly increased thymus weight and total CD4+ T cell numbers in SOD1(G93A) mice, although Tregs levels were not affected. Despite this, disease onset and progression were similar in castrated and sham SOD1(G93A) mice. Castration did not affect motor neuron loss or astrocytic activation in spinal cords of SOD1(G93A) mice; however, microglial activation was reduced, specifically M1 microglia. We also show that AR is principally expressed in spinal motor neurons and progressively downregulated in spinal cords of SOD1(G93A) mice from disease onset which is further enhanced by castration. CONCLUSIONS: These results demonstrate that increasing thymic function and CD4+ T cell number by castration confers no clinical benefit in mutant SOD1 mice, which may reflect an inability to stimulate neuroprotective Tregs. Nonetheless, castration decreases M1 microglial activation in the spi

Published
2015

11. Mutant TDP-43 Deregulates AMPK Activation by PP2A in ALS Models (vol 9, e90449, 2014)

Author

Perera, ND, Sheean, RK, Scott, JW, Kemp, BE, Horne, MK, Perera, ND, Sheean, RK, Scott, JW, Kemp, BE, and Horne, MK

Abstract

Bioenergetic abnormalities and metabolic dysfunction occur in amyotrophic lateral sclerosis (ALS) patients and genetic mouse models. However, whether metabolic dysfunction occurs early in ALS pathophysiology linked to different ALS genes remains unclear. Here, we investigated AMP-activated protein kinase (AMPK) activation, which is a key enzyme induced by energy depletion and metabolic stress, in neuronal cells and mouse models expressing mutant superoxide dismutase 1 (SOD1) or TAR DNA binding protein 43 (TDP-43) linked to ALS. AMPK phosphorylation was sharply increased in spinal cords of transgenic SOD1G93A mice at disease onset and accumulated in cytoplasmic granules in motor neurons, but not in presymptomatic mice. AMPK phosphorylation also occurred in peripheral tissues, liver and kidney, in SOD1G93A mice at disease onset, demonstrating that AMPK activation occurs late and is not restricted to motor neurons. Conversely, AMPK activity was drastically diminished in spinal cords and brains of presymptomatic and symptomatic transgenic TDP-43A315T mice and motor neuronal cells expressing different TDP-43 mutants. We show that mutant TDP-43 induction of the AMPK phosphatase, protein phosphatase 2A (PP2A), is associated with AMPK inactivation in these ALS models. Furthermore, PP2A inhibition by okadaic acid reversed AMPK inactivation by mutant TDP-43 in neuronal cells. Our results suggest that mutant SOD1 and TDP-43 exert contrasting effects on AMPK activation which may reflect key differences in energy metabolism and neurodegeneration in spinal cords of SOD1G93A and TDP-43A315T mice. While AMPK activation in motor neurons correlates with progression in mutant SOD1-mediated disease, AMPK inactivation mediated by PP2A is associated with mutant TDP-43-linked ALS.

Published
2014

12. Mutant TDP-43 Deregulates AMPK Activation by PP2A in ALS Models

Author

Sensi, SL, Perera, ND, Sheean, RK, Scott, JW, Kemp, BE, Horne, MK, Turner, BJ, Sensi, SL, Perera, ND, Sheean, RK, Scott, JW, Kemp, BE, Horne, MK, and Turner, BJ

Abstract

Bioenergetic abnormalities and metabolic dysfunctionoccur in amyotrophic lateral sclerosis (ALS) patients and genetic mouse models. However, whether metabolic dysfunction occurs earlyin ALS pathophysiology linked to different ALS genes remains unclear.Here, we investigatedAMP-activated protein kinase (AMPK) activation, which is a key enzyme induced by energy depletion and metabolic stress, inneuronal cells and mouse models expressing mutantsuperoxide dismutase 1 (SOD1)or TAR DNA binding protein 43 (TDP-43) linked to ALS.AMPKphosphorylation was sharply increased in spinal cords of transgenic SOD1G93A mice at disease onset and accumulated incytoplasmic granules in motor neurons, but not in pre-symptomatic mice. AMPK phosphorylation also occurred in peripheraltissues, liver and kidney, in SOD1G93A mice at disease onset, demonstrating that AMPK activation occurs late and is not restricted to motor neurons. Conversely, AMPK activity was drastically diminished in spinal cords and brains of presymptomatic and symptomatictransgenic TDP-43A315T mice and motor neuronal cells expressing different TDP-43 mutants. We show that mutant TDP-43 induction of the AMPK phosphatase,protein phosphatase 2A (PP2A), is associated with AMPK inactivation in these ALS models. Furthermore, PP2A inhibition by okadaic acid reversed AMPK inactivation by mutant TDP-43 in neuronal cells. Our results suggest that mutant SOD1 and TDP-43 exert contrasting effects on AMPK activation which may reflect key differences in energy metabolism and neurodegeneration in spinal cords of SOD1G93A and TDP-43A315T mice. While AMPK activation in motor neurons correlateswith progressionin mutant SOD1-mediated disease, AMPK inactivation mediated by PP2Ais associated withmutant TDP-43-linked ALS.

Published
2014

23. Virchow's node

Author

Senevirathna, LN, primary, Jayasundare, JMNRK, additional, and Perera, ND, additional

Published
2010
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29. Depth of Response From Fixed-Duration Treatment Is Associated With Superior Survival in Waldenstrom Macroglobulinemia.

Author

Paludo J, Abeykoon JP, Perera ND, Sarosiek S, Gustine J, Ramirez-Gamero A, Varettoni M, Tedeschi A, Cavalloni C, Frustaci AM, Pederson LD, Zanwar SS, Kapoor P, Habermann TM, Witzig TE, Kyle RA, Gertz MA, Geyer SM, Treon SP, Castillo JJ, and Ansell SM

Abstract

As the treatment paradigm for Waldenström macroglobulinemia (WM) continues to evolve, the debate surrounding the prioritization of depth of response versus disease control as therapeutic goals gains significant relevance. However, the impact of depth of response from fixed-duration therapy on overall survival (OS) was unclear. This multicenter study evaluated the prognostic impact of depth of response using a landmark survival analysis. A total of 440 patients with WM treated with frontline fixed-duration regimens were included. Attaining a major response (MaR) was associated with superior outcomes, including significantly longer OS. The estimated 5-year PFS rates for patients with MaR at 6 months versus not were 50% versus 32%, respectively, p < 0.001, and the estimated 5-year OS rates for patients with MaR at 6 months versus not were 89% versus 70%, respectively, p < 0.001. In a multivariable analysis, MaR at 6 months was independently associated with superior PFS (HR 0.66, p = 0.007) and OS (HR 0.28, p < 0.001). Similar results were seen when considering deeper responses (CR + VGPR vs. PR). Depth of response at 6 months is an important prognostic marker in WM and an independent predictor of PFS and OS. These results support its utilization as a suitable endpoint in clinical studies in WM., (© 2025 Wiley Periodicals LLC.)

Published
2025
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30. IGFBP5 as a Novel Basolateral Secretion Marker in the Retinal Pigment Epithelium.

Author

Digsby KM, Zhang Q, Perera ND, Karoukis A, DenDekker A, Fahim AT, and Miller JML

Subjects
Humans, Animals, Cell Polarity, Cells, Cultured, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium cytology, Tissue Inhibitor of Metalloproteinase-3 metabolism, Tissue Inhibitor of Metalloproteinase-3 genetics, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A analysis, Biomarkers metabolism, Insulin-Like Growth Factor Binding Protein 5 metabolism, Insulin-Like Growth Factor Binding Protein 5 genetics
Abstract

The retinal pigment epithelium (RPE) is a highly polarized cell type in the retina which is specialized to support the photoreceptors and choroid. To assess the adequacy of RPE polarity in culture or altered RPE polarity under disease conditions in vivo, the polarized secretion of particular proteins can be monitored. Currently accepted basolateral secretion markers for RPE include the pro-angiogenic factor, VEGF, and extracellular matrix remodeling protein, TIMP-3. However, VEGF secretion is low enough that it often requires ELISA for detection, and TIMP-3 secretion is only modestly polarized to the basolateral side. We sought out an improved marker of basolateral secretion that is both highly expressed and highly polarized. Through a combination of bioinformatics analysis and RPE cell culture experiments, we identify insulin growth factor binding protein 5 (IGFBP5) as a more robust and convenient RPE basolateral marker compared to TIMP-3 and VEGF., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Published
2025
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31. State-Dependent Motor Cortex Stimulation Reveals Distinct Mechanisms for Corticospinal Excitability and Cortical Responses.

Author

Perera ND, Wischnewski M, Alekseichuk I, Shirinpour S, and Opitz A

Subjects
Humans, Female, Male, Adult, Young Adult, Electromyography, Motor Cortex physiology, Transcranial Magnetic Stimulation, Evoked Potentials, Motor physiology, Pyramidal Tracts physiology, Electroencephalography
Abstract

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that modulates brain activity by inducing electric fields in the brain. Real-time, state-dependent stimulation with TMS has shown that neural oscillation phase modulates corticospinal excitability. However, such motor evoked potentials (MEPs) only indirectly reflect motor cortex activation and are unavailable at other brain regions of interest. The direct and secondary cortical effects of phase-dependent brain stimulation remain an open question. In this study, we recorded the cortical responses during single-pulse TMS using electroencephalography (EEG) concurrently with the MEP measurements in 20 healthy human volunteers (11 female). TMS was delivered at peak, rising, trough, and falling phases of mu (8-13 Hz) and beta (14-30 Hz) oscillations in the motor cortex. The cortical responses were quantified through TMS evoked potential components N15, P50, and N100 as peak-to-peak amplitudes (P50-N15 and P50-N100). We further analyzed whether the prestimulus frequency band power was predictive of the cortical responses. We demonstrated that phase-specific targeting modulates cortical responses. The phase relationship between cortical responses was different for early and late responses. In addition, pre-TMS mu oscillatory power and phase significantly predicted both early and late cortical EEG responses in mu-specific targeting, indicating the independent causal effects of phase and power. However, only pre-TMS beta power significantly predicted the early and late TEP components during beta-specific targeting. Further analyses indicated distinct roles of mu and beta power on cortical responses. These findings provide insight to mechanistic understanding of neural oscillation states in cortical and corticospinal activation in humans., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Perera et al.)

Published
2024
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32. Systemic administration of a novel Beclin 1-derived peptide significantly upregulates autophagy in the spinal motor neurons of autophagy reporter mice.

Author

Amin A, Perera ND, Tomas D, Cuic B, Radwan M, Hatters DM, Turner BJ, and Shabanpoor F

Subjects
Animals, Mice, Spinal Cord drug effects, Spinal Cord metabolism, Peptides pharmacology, Peptides administration & dosage, Peptides chemistry, Cell-Penetrating Peptides administration & dosage, Cell-Penetrating Peptides chemistry, Humans, Male, Protein Aggregates drug effects, Autophagy drug effects, Beclin-1 metabolism, Motor Neurons drug effects, Up-Regulation drug effects
Abstract

Autophagy, an intracellular degradation system, plays a vital role in protecting cells by clearing damaged organelles, pathogens, and protein aggregates. Autophagy upregulation through pharmacological interventions has gained significant attention as a potential therapeutic avenue for proteinopathies. Here, we report the development of an autophagy-inducing peptide (BCN4) derived from the Beclin 1 protein, the master regulator of autophagy. To deliver the BCN4 into cells and the central nervous system (CNS), it was conjugated to our previously developed cell and blood-brain barrier-penetrating peptide (CPP). CPP-BCN4 significantly upregulated autophagy and reduced protein aggregates in motor neuron (MN)-like cells. Moreover, its systemic administration in a reporter mouse model of autophagy resulted in a significant increase in autophagy activity in the spinal MNs. Therefore, this novel autophagy-inducing peptide with a demonstrated ability to upregulate autophagy in the CNS has significant potential for the treatment of various neurodegenerative diseases with protein aggregates as a characteristic feature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Published
2024
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33. Reduced Retinal Pigment Epithelial Autophagy Due to Loss of Rab12 Prenylation in a Human iPSC-RPE Model of Choroideremia.

Author

Raeker MÖ, Perera ND, Karoukis AJ, Chen L, Feathers KL, Ali RR, Thompson DA, and Fahim AT

Subjects
Humans, Adaptor Proteins, Signal Transducing, Mechanistic Target of Rapamycin Complex 1 metabolism, Models, Biological, Signal Transduction, Autophagy, Choroideremia pathology, Choroideremia genetics, Choroideremia metabolism, Induced Pluripotent Stem Cells metabolism, rab GTP-Binding Proteins metabolism, rab GTP-Binding Proteins genetics, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium pathology
Abstract

Choroideremia is an X-linked chorioretinal dystrophy caused by mutations in CHM , encoding Rab escort protein 1 (REP-1), leading to under-prenylation of Rab GTPases (Rabs). Despite ubiquitous expression of CHM , the phenotype is limited to degeneration of the retina, retinal pigment epithelium (RPE), and choroid, with evidence for primary pathology in RPE cells. However, the spectrum of under-prenylated Rabs in RPE cells and how they contribute to RPE dysfunction remain unknown. A CRISPR/Cas-9-edited CHM -/- iPSC-RPE model was generated with isogenic control cells. Unprenylated Rabs were biotinylated in vitro and identified by tandem mass tag (TMT) spectrometry. Rab12 was one of the least prenylated and has an established role in suppressing mTORC1 signaling and promoting autophagy. CHM -/- iPSC-RPE cells demonstrated increased mTORC1 signaling and reduced autophagic flux, consistent with Rab12 dysfunction. Autophagic flux was rescued in CHM -/- cells by transduction with gene replacement (ShH10-CMV- CHM ) and was reduced in control cells by siRNA knockdown of Rab12. This study supports Rab12 under-prenylation as an important cause of RPE cell dysfunction in choroideremia and highlights increased mTORC1 and reduced autophagy as potential disease pathways for further investigation.

Published
2024
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34. Multimodal Imaging-Guided Stem Cell Ocular Treatment.

Author

Nguyen VP, Karoukis AJ, Qian W, Chen L, Perera ND, Yang D, Zhang Q, Zhe J, Henry J, Liu B, Zhang W, Fahim AT, Wang X, and Paulus YM

Subjects
Rabbits, Animals, Humans, Stem Cell Transplantation, Tomography, Optical Coherence, Metal Nanoparticles chemistry, Induced Pluripotent Stem Cells cytology, Cell Movement, Cell Differentiation, Optical Imaging, Photoacoustic Techniques, Multimodal Imaging, Gold chemistry, Retinal Pigment Epithelium cytology
Abstract

Stem cell therapies are gaining traction as promising treatments for a variety of degenerative conditions. Both clinical and preclinical studies of regenerative medicine are hampered by the lack of technologies that can evaluate the migration and behavior of stem cells post-transplantation. This study proposes an innovative method to longitudinally image in vivo human-induced pluripotent stem cells differentiated to retinal pigment epithelium (hiPSC-RPE) cells by multimodal photoacoustic microscopy, optical coherence tomography, and fluorescence imaging powered by ultraminiature chain-like gold nanoparticle cluster (GNC) nanosensors. The GNC exhibits an optical absorption peak in the near-infrared regime, and the 7-8 nm size in diameter after disassembly enables renal excretion and improved safety as well as biocompatibility. In a clinically relevant rabbit model, GNC-labeled hiPSC-RPE cells migrated to RPE degeneration areas and regenerated damaged tissues. The hiPSC-RPE cells' distribution and migration were noninvasively, longitudinally monitored for 6 months with exceptional sensitivity and spatial resolution. This advanced platform for cellular imaging has the potential to enhance regenerative cell-based therapies.

Published
2024
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36. Induced neural phase precession through exogenous electric fields.

Author

Wischnewski M, Tran H, Zhao Z, Shirinpour S, Haigh ZJ, Rotteveel J, Perera ND, Alekseichuk I, Zimmermann J, and Opitz A

Subjects
Animals, Primates, Action Potentials physiology, Neurons physiology, Brain
Abstract

The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by ~90°. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons (~30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods., (© 2024. The Author(s).)

Published
2024
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37. Dissociation of Centrally and Peripherally Induced Transcranial Magnetic Stimulation Effects in Nonhuman Primates.

Author

Perera ND, Alekseichuk I, Shirinpour S, Wischnewski M, Linn G, Masiello K, Butler B, Russ BE, Schroeder CE, Falchier A, and Opitz A

Subjects
Male, Humans, Female, Animals, Macaca mulatta, Evoked Potentials physiology, Biomarkers, Evoked Potentials, Motor physiology, Transcranial Magnetic Stimulation methods, Electroencephalography methods
Abstract

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation method that is rapidly growing in popularity for studying causal brain-behavior relationships. However, its dose-dependent centrally induced neural mechanisms and peripherally induced sensory costimulation effects remain debated. Understanding how TMS stimulation parameters affect brain responses is vital for the rational design of TMS protocols. Studying these mechanisms in humans is challenging because of the limited spatiotemporal resolution of available noninvasive neuroimaging methods. Here, we leverage invasive recordings of local field potentials in a male and a female nonhuman primate (rhesus macaque) to study TMS mesoscale responses. We demonstrate that early TMS-evoked potentials show a sigmoidal dose-response curve with stimulation intensity. We further show that stimulation responses are spatially specific. We use several control conditions to dissociate centrally induced neural responses from auditory and somatosensory coactivation. These results provide crucial evidence regarding TMS neural effects at the brain circuit level. Our findings are highly relevant for interpreting human TMS studies and biomarker developments for TMS target engagement in clinical applications. SIGNIFICANCE STATEMENT Transcranial magnetic stimulation (TMS) is a widely used noninvasive brain stimulation method to stimulate the human brain. To advance its utility for clinical applications, a clear understanding of its underlying physiological mechanisms is crucial. Here, we perform invasive electrophysiological recordings in the nonhuman primate brain during TMS, achieving a spatiotemporal precision not available in human EEG experiments. We find that evoked potentials are dose dependent and spatially specific, and can be separated from peripheral stimulation effects. This means that TMS-evoked responses can indicate a direct physiological stimulation response. Our work has important implications for the interpretation of human TMS-EEG recordings and biomarker development., (Copyright © 2023 the authors.)

Published
2023
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38. Age-related deficits in retinal autophagy following intraocular pressure elevation in autophagy reporter mouse model.

Author

Afiat BC, Zhao D, Wong VHY, Perera ND, Turner BJ, Nguyen CTO, and Bui BV

Subjects
Mice, Animals, Retinal Ganglion Cells physiology, Disease Models, Animal, Mice, Transgenic, Autophagy genetics, Intraocular Pressure, Retina
Abstract

This study quantified age-related changes to retinal autophagy using the CAG-RFP-EGFP-LC3 autophagy reporter mice and considered how aging impacts autophagic responses to acute intraocular pressure (IOP) stress. IOP was elevated to 50 mm Hg for 30 minutes in 3-month-old and 12-month-old CAG-RFP-EGFP-LC3 (n = 7 per age group) and Thy1-YFPh transgenic mice (n = 3 per age group). Compared with younger eyes, older eyes showed diminished basal autophagy in the outer retina, while the inner retina was unaffected. Autophagic flux (red:yellow puncta ratio) was elevated in the inner plexiform layer. Three days following IOP elevation, older eyes showed poorer functional recovery, most notably in ganglion cell responses compared to younger eyes (12 months old: -33.4 ± 5.3% vs. 3 months mice: -13.4 ± 4.5%). This paralleled a reduced capacity to upregulate autophagic puncta volume in the inner retina in older eyes, a response that was seen in younger eyes. Age-related decline in basal and stress-induced autophagy in the retina is associated with greater retinal ganglion cells' susceptibility to IOP elevation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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39. Induced neural phase precession through exogeneous electric fields.

Author

Wischnewski M, Tran H, Zhao Z, Shirinpour S, Haigh ZJ, Rotteveel J, Perera ND, Alekseichuk I, Zimmermann J, and Opitz A

Abstract

The gradual shifting of preferred neural spiking relative to local field potentials (LFPs), known as phase precession, plays a prominent role in neural coding. Correlations between the phase precession and behavior have been observed throughout various brain regions. As such, phase precession is suggested to be a global neural mechanism that promotes local neuroplasticity. However, causal evidence and neuroplastic mechanisms of phase precession are lacking so far. Here we show a causal link between LFP dynamics and phase precession. In three experiments, we modulated LFPs in humans, a non-human primate, and computational models using alternating current stimulation. We show that continuous stimulation of motor cortex oscillations in humans lead to a gradual phase shift of maximal corticospinal excitability by ~90°. Further, exogenous alternating current stimulation induced phase precession in a subset of entrained neurons (~30%) in the non-human primate. Multiscale modeling of realistic neural circuits suggests that alternating current stimulation-induced phase precession is driven by NMDA-mediated synaptic plasticity. Altogether, the three experiments provide mechanistic and causal evidence for phase precession as a global neocortical process. Alternating current-induced phase precession and consequently synaptic plasticity is crucial for the development of novel therapeutic neuromodulation methods.

Published
2023
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40. Anatomical details affect electric field predictions for non-invasive brain stimulation in non-human primates.

Author

Mantell KE, Perera ND, Shirinpour S, Puonti O, Xu T, Zimmermann J, Falchier A, Heilbronner SR, Thielscher A, and Opitz A

Subjects
Animals, Humans, Anisotropy, Computer Simulation, Brain, Primates, Electricity
Abstract

Non-human primates (NHPs) have become key for translational research in noninvasive brain stimulation (NIBS). However, in order to create comparable stimulation conditions for humans it is vital to study the accuracy of current modeling practices across species. Numerical models to simulate electric fields are an important tool for experimental planning in NHPs and translation to human studies. It is thus essential whether and to what extent the anatomical details of NHP models agree with current modeling practices when calculating NIBS electric fields. Here, we create highly accurate head models of two non-human primates (NHP) MR data. We evaluate how muscle tissue and head field of view (depending on MRI parameters) affect simulation results in transcranial electric and magnetic stimulation (TES and TMS). Our findings indicate that the inclusion of anisotropic muscle can affect TES electric field strength up to 22% while TMS is largely unaffected. Additionally, comparing a full head model to a cropped head model illustrates the impact of head field of view on electric fields for both TES and TMS. We find opposing effects between TES and TMS with an increase up to 24.8% for TES and a decrease up to 24.6% for TMS for the cropped head model compared to the full head model. Our results provide important insights into the level of anatomical detail needed for NHP head models and can inform future translational efforts for NIBS studies., Competing Interests: Declaration of Competing Interest Declarations of interest: none, (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2023
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42. Long-term outcomes of allogeneic stem cell transplant in multiple myeloma.

Author

Schmidt WM, Perera ND, Buadi FK, Hayman SR, Kumar SK, Dispenzieri A, Dingli D, Cook J, Lacy MQ, Kapoor P, Leung N, Muchtar E, Warsame RM, Kourelis T, Binder M, Gonsalves WI, Hogan WJ, and Gertz MA

Subjects
Humans, Retrospective Studies, Progression-Free Survival, Stem Cell Transplantation, Multiple Myeloma therapy, Hematopoietic Stem Cell Transplantation
Abstract

Allogeneic stem cell transplant (allo SCT) for multiple myeloma (MM) is potentially curative in some, while toxic in many others. We retrospectively analyzed 85 patients diagnosed with MM who underwent allo SCT as frontline or salvage therapy between 2000 and 2022 at Mayo Clinic Rochester and examined patient outcomes and prognostic markers. Overall survival (OS), progression free survival (PFS), treatment related mortality (TRM), and relapse rates (RR) were estimated using the Kaplan Meier method and competing risk models. Median follow-up was 11.5 years. Median OS and PFS were 1.7 and 0.71 years, respectively. Five-year OS and PFS were 22.2% and 15.1%, respectively. One-year TRM was 23.5%. Twelve patients demonstrated durable overall survival, living 10+ years beyond their allo SCT. This subgroup was more likely to have no or one prior auto SCT (p = 0.03) and to have been transplanted between 2000 and 2010 (p = 0.03). Outcomes were poor in this cohort with long follow-up, with few patients surviving 5 years or more, and most relapsing or dying within 2 years. We would expect better outcomes and tolerability with an expanded array of novel therapeutics and would prefer them to allo SCT., (© 2023. Springer Nature Limited.)

Published
2023
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43. Analysis of Female Participant Representation in Registered Oncology Clinical Trials in the United States from 2008 to 2020.

Author

Perera ND, Bellomo TR, Schmidt WM, Litt HK, Shyu M, Stavins MA, Wang MM, Bell A, Saleki M, Wolf KI, Ionescu R, Tao JJ, Ji S, O'Keefe RM, Pun M, Takasugi JM, Steinberg JR, Go RS, Turner BE, and Mahipal A

Subjects
Male, Humans, Female, United States epidemiology, Medical Oncology, Odds Ratio, Databases, Factual, Prevalence, Neoplasms epidemiology, Neoplasms therapy
Abstract

Background: Female underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding., Materials and Methods: Data were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation., Results: Females represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P < .01), stomach (OR 0.40, 95% CI 0.23-0.70, P < .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P < .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P < .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P < .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials., Conclusions: Stakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results., (© The Author(s) 2023. Published by Oxford University Press.)

Published
2023
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44. Clinical Exome Gene Panel Analysis of a Cohort of Urothelial Bladder Cancer Patients from Sri Lanka.

Author

Malalasekera A, Neththikumara N, Somasundaram P, Pathirana S, Ediriweera C, Ediriweera D, Goonewardena SA, Perera ND, Abeygunasekara A, Jayasekara RW, Wettasinghe K, Lokuhetty MDS, and Dissanayeke VHW

Subjects
Humans, Exome, Sri Lanka, Mutation, Urinary Bladder Neoplasms pathology, Carcinoma, Transitional Cell pathology
Abstract

Background: Bladder cancer has a high rate of recurrence and high mortality rates in those who progress to muscle invasive disease. Biomarkers and molecular sub classification of tumours beyond standard histopathology has been proposed to address therapeutic dilemmas. The Cancer Genome Atlas project and other studies have contributed to the enhanced knowledge base of the mutational landscape of urothelial bladder cancer. Once again, these are mostly from Caucasian and Chinese patients, with data from the rest of Asia and Sri Lanka being sparse. The objective of this study was to assess the genomic variations of a cohort of urothelial bladder cancer patients in Sri Lanka., Methods: The molecular genetic study was conducted on formalin fixed paraffin embedded tumour samples of 24 patients, prospectively enrolled from 2013 to 2017. The samples were sequenced and variant distribution performed based on a 70-gene panel., Results: Total number of filtered mutations in the 24 patients was 10453. Median mutations per patient were 450 (range 22-987). The predominant mutational change was C>T and G>A. The top 5 mutated genes in our cohort were SYNE1, SYNE2, KMT2C, LRP2, and ANK2. The genes were clustered into 3 groups dependent on the number of mutations per patient per gene. The genes of cluster 1 and 2 mapped to Chromatin modifying enzymes and Generic Transcription Pathway. The chromatin remodelling pathway accounted for the largest proportion (22%) of mutations., Conclusions: Clinical exome sequencing utilising a gene panel yielded a high mutation rate in our patients. The predominant mutational change was C>T and G>A. Three clusters of genes were identified. SYNE1 was the gene with the most mutations. The mutations comprised predominantly of genes of the chromatin remodelling pathway.

Published
2023
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46. The Evolving Therapeutic Landscape for Malignant Pleural Mesothelioma.

Author

Perera ND and Mansfield AS

Subjects
Humans, Immune Checkpoint Inhibitors, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Vascular Endothelial Growth Factor A, Immunotherapy, Receptor Protein-Tyrosine Kinases, Mesothelioma, Malignant, Pleural Neoplasms drug therapy, Pleural Neoplasms pathology, Lung Neoplasms drug therapy, Mesothelioma drug therapy, Mesothelioma pathology
Abstract

Purpose of Review: For patients with malignant pleural mesothelioma, prognosis is poor with extremely low 5-year survival rates and limited therapeutic options. Here, we review the current treatment landscape for mesothelioma and highlight promising future therapeutic directions., Recent Findings: Evolving frontline therapeutic options for mesothelioma include VEGF inhibition in combination with chemotherapy and dual immune checkpoint inhibition, with synergisms between the therapies and response prediction via biomarkers also being explored. Evolving experimental treatments for mesothelioma include PARP and ALK inhibitors, dendritic and CAR T-cell therapies, anti-mesothelin vaccines, and oncolytic viral therapies, representing timely advances in the field. The therapeutic landscape for malignant pleural mesothelioma is evolving and preferred treatment in the frontline and later settings will likely evolve with it. However, this does not preclude the evidence for including multi-modal therapies spanning angiogenesis and immune checkpoint inhibitors, and biomarker utilization, in current clinical trials and management., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2022
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47. Oxidative stress differentially impacts apical and basolateral secretion of angiogenic factors from human iPSC-derived retinal pigment epithelium cells.

Author

Chen L, Perera ND, Karoukis AJ, Feathers KL, Ali RR, Thompson DA, and Fahim AT

Subjects
Angiogenesis Inducing Agents pharmacology, Cells, Cultured, Humans, Hydrogen Peroxide metabolism, Oxidative Stress, Retinal Pigment Epithelium metabolism, Vascular Endothelial Growth Factor A metabolism, Induced Pluripotent Stem Cells metabolism, Macular Degeneration pathology
Abstract

The retinal pigment epithelium (RPE) is a polarized monolayer that secretes growth factors and cytokines towards the retina apically and the choroid basolaterally. Numerous RPE secreted proteins have been linked to the pathogenesis of age-related macular degeneration (AMD). The purpose of this study was to determine the differential apical and basolateral secretome of RPE cells, and the effects of oxidative stress on directional secretion of proteins linked to AMD and angiogenesis. Tandem mass tag spectrometry was used to profile proteins in human iPSC-RPE apical and basolateral conditioned media. Changes in secretion after oxidative stress induced by H 2 O 2 or tert-butyl hydroperoxide (tBH) were investigated by ELISA and western analysis. Out of 926 differentially secreted proteins, 890 (96%) were more apical. Oxidative stress altered the secretion of multiple factors implicated in AMD and neovascularization and promoted a pro-angiogenic microenvironment by increasing the secretion of pro-angiogenic molecules (VEGF, PTN, and CRYAB) and decreasing the secretion of anti-angiogenic molecules (PEDF and CFH). Apical secretion was impacted more than basolateral for PEDF, CRYAB and CFH, while basolateral secretion was impacted more for VEGF, which may have implications for choroidal neovascularization. This study lays a foundation for investigations of dysfunctional RPE polarized protein secretion in AMD and other chorioretinal degenerative disorders., (© 2022. The Author(s).)

Published
2022
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49. Metabolic Dysfunction in Motor Neuron Disease: Shedding Light through the Lens of Autophagy.

Author

De Silva S, Turner BJ, and Perera ND

Abstract

Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.

Published
2022
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50. Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis.

Author

Wang T, Tomas D, Perera ND, Cuic B, Luikinga S, Viden A, Barton SK, McLean CA, Samson AL, Southon A, Bush AI, Murphy JM, and Turner BJ

Subjects
Animals, Cell Death physiology, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Motor Neurons metabolism, Spinal Cord metabolism, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 metabolism, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Ferroptosis
Abstract

Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1 G93A ), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1 G93A mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment., (© 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Published
2022
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