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4. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author

Perenthaler, Elena, Nikoncuk, Anita, Yousefi, Soheil, Berdowski, Woutje M., Alsagob, Maysoon, Capo, Ivan, van der Linde, Herma C., van den Berg, Paul, Jacobs, Edwin H., Putar, Darija, Ghazvini, Mehrnaz, Aronica, Eleonora, van IJcken, Wilfred F. J., de Valk, Walter G., Medici-van den Herik, Evita, van Slegtenhorst, Marjon, Brick, Lauren, Kozenko, Mariya, Kohler, Jennefer N., Bernstein, Jonathan A., Monaghan, Kristin G., Begtrup, Amber, Torene, Rebecca, Al Futaisi, Amna, Al Murshedi, Fathiya, Mani, Renjith, Al Azri, Faisal, Kamsteeg, Erik-Jan, Mojarrad, Majid, Eslahi, Atieh, Khazaei, Zaynab, Darmiyan, Fateme Massinaei, Doosti, Mohammad, Karimiani, Ehsan Ghayoor, Vandrovcova, Jana, Zafar, Faisal, Rana, Nuzhat, Kandaswamy, Krishna K., Hertecant, Jozef, Bauer, Peter, AlMuhaizea, Mohammed A., Salih, Mustafa A., Aldosary, Mazhor, Almass, Rawan, Al-Quait, Laila, Qubbaj, Wafa, Coskun, Serdar, Alahmadi, Khaled O., Hamad, Muddathir H. A., Alwadaee, Salem, Awartani, Khalid, Dababo, Anas M., Almohanna, Futwan, Colak, Dilek, Dehghani, Mohammadreza, Mehrjardi, Mohammad Yahya Vahidi, Gunel, Murat, Ercan-Sencicek, A. Gulhan, Passi, Gouri Rao, Cheema, Huma Arshad, Efthymiou, Stephanie, Houlden, Henry, Bertoli-Avella, Aida M., Brooks, Alice S., Retterer, Kyle, Maroofian, Reza, Kaya, Namik, van Ham, Tjakko J., and Barakat, Tahsin Stefan

Published
2020
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7. Additional file 1 of Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance

Author

Yousefi, Soheil, Deng, Ruizhi, Lanko, Kristina, Salsench, Eva Medico, Nikoncuk, Anita, van der Linde, Herma C., Perenthaler, Elena, van Ham, Tjakko J., Mulugeta, Eskeatnaf, and Barakat, Tahsin Stefan

Abstract

Additional file 1: Fig. S1: Flow chart of integrative data analysis; Fig. S2: Derivation of pCRs and DAEs; Fig. S3: Enhancer-Gene predictions and target gene expression; Fig. S4: Features and motifs in DAEs and nDAEs; Fig. S5: Cell type specificity of DAEs and nDAEs; Fig. S6: Dynamics of DAEs and nDAEs in comparison to adult brain; Fig. S7: DAEs and nDAEs in human disease, related to Fig. 5; Fig. S8: Zebrafish enhancer reporter assay

Published
2021
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8. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Author

Sanderson, Leslie E., Lanko, Kristina, Alsagob, Maysoon, Almass, Rawan, Al-Ahmadi, Nada, Najafi, Maryam, Al-Muhaizea, Mohammad A., Alzaidan, Hamad, Aldhalaan, Hesham, Perenthaler, Elena, Van Der Linde, Herma C., Nikoncuk, Anita, Kühn, Nikolas A., Antony, Dinu, Owaidah, Tarek Mustafa, Raskin, Salmo, Vieira, Luana Gabriela Dalla Rosa, Mombach, Romulo, Ahangari, Najmeh, Silveira, Tainá Regina Damaceno, Ameziane, Najim, Rolfs, Arndt, Alharbi, Aljohara, Sabbagh, Raghda M., Alahmadi, Khalid, Alawam, Bashayer, Ghebeh, Hazem, Alhargan, Aljouhra, Albader, Anoud A., Binhumaid, Faisal S., Goljan, Ewa, Monies, Dorota, Mustafa, Osama M., Aldosary, Mazhor, Albakheet, Albandary, Alyounes, Banan, Almutairi, Faten, Al-Odaib, Ali, Aksoy, Durdane Bekar, Basak, A. Nazli, Palvadeau, Robin, Trabzuni, Daniah, Rosenfeld, Jill A., Karimiani, Ehsan Ghayoor, Meyer, Brian F., Karakas, Bedri, Al-Mohanna, Futwan, Arold, Stefan T., Colak, Dilek, Maroofian, Reza, Houlden, Henry, Bertoli-Avella, Aida M., Schmidts, Miriam, Barakat, Tahsin Stefan, Van Ham, Tjakko J., Kaya, Namik, Sanderson, Leslie E., Lanko, Kristina, Alsagob, Maysoon, Almass, Rawan, Al-Ahmadi, Nada, Najafi, Maryam, Al-Muhaizea, Mohammad A., Alzaidan, Hamad, Aldhalaan, Hesham, Perenthaler, Elena, Van Der Linde, Herma C., Nikoncuk, Anita, Kühn, Nikolas A., Antony, Dinu, Owaidah, Tarek Mustafa, Raskin, Salmo, Vieira, Luana Gabriela Dalla Rosa, Mombach, Romulo, Ahangari, Najmeh, Silveira, Tainá Regina Damaceno, Ameziane, Najim, Rolfs, Arndt, Alharbi, Aljohara, Sabbagh, Raghda M., Alahmadi, Khalid, Alawam, Bashayer, Ghebeh, Hazem, Alhargan, Aljouhra, Albader, Anoud A., Binhumaid, Faisal S., Goljan, Ewa, Monies, Dorota, Mustafa, Osama M., Aldosary, Mazhor, Albakheet, Albandary, Alyounes, Banan, Almutairi, Faten, Al-Odaib, Ali, Aksoy, Durdane Bekar, Basak, A. Nazli, Palvadeau, Robin, Trabzuni, Daniah, Rosenfeld, Jill A., Karimiani, Ehsan Ghayoor, Meyer, Brian F., Karakas, Bedri, Al-Mohanna, Futwan, Arold, Stefan T., Colak, Dilek, Maroofian, Reza, Houlden, Henry, Bertoli-Avella, Aida M., Schmidts, Miriam, Barakat, Tahsin Stefan, Van Ham, Tjakko J., and Kaya, Namik

Abstract

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

Published
2021

9. Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance

Author

Yousefi, Soheil, primary, Deng, Ruizhi, additional, Lanko, Kristina, additional, Salsench, Eva Medico, additional, Nikoncuk, Anita, additional, van der Linde, Herma C., additional, Perenthaler, Elena, additional, van Ham, Tjakko, additional, Mulugeta, Eskeatnaf, additional, and Barakat, Tahsin Stefan, additional

Published
2021
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10. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Author

Sanderson, Leslie E, primary, Lanko, Kristina, additional, Alsagob, Maysoon, additional, Almass, Rawan, additional, Al-Ahmadi, Nada, additional, Najafi, Maryam, additional, Al-Muhaizea, Mohammad A, additional, Alzaidan, Hamad, additional, AlDhalaan, Hesham, additional, Perenthaler, Elena, additional, van der Linde, Herma C, additional, Nikoncuk, Anita, additional, Kühn, Nikolas A, additional, Antony, Dinu, additional, Owaidah, Tarek Mustafa, additional, Raskin, Salmo, additional, Vieira, Luana Gabriela Dalla Rosa, additional, Mombach, Romulo, additional, Ahangari, Najmeh, additional, Silveira, Tainá Regina Damaceno, additional, Ameziane, Najim, additional, Rolfs, Arndt, additional, Alharbi, Aljohara, additional, Sabbagh, Raghda M, additional, AlAhmadi, Khalid, additional, Alawam, Bashayer, additional, Ghebeh, Hazem, additional, AlHargan, Aljouhra, additional, Albader, Anoud A, additional, Binhumaid, Faisal S, additional, Goljan, Ewa, additional, Monies, Dorota, additional, Mustafa, Osama M, additional, Aldosary, Mazhor, additional, AlBakheet, Albandary, additional, Alyounes, Banan, additional, Almutairi, Faten, additional, Al-Odaib, Ali, additional, Aksoy, Durdane Bekar, additional, Basak, A Nazli, additional, Palvadeau, Robin, additional, Trabzuni, Daniah, additional, Rosenfeld, Jill A, additional, Karimiani, Ehsan Ghayoor, additional, Meyer, Brian F, additional, Karakas, Bedri, additional, Al-Mohanna, Futwan, additional, Arold, Stefan T, additional, Colak, Dilek, additional, Maroofian, Reza, additional, Houlden, Henry, additional, Bertoli-Avella, Aida M, additional, Schmidts, Miriam, additional, Barakat, Tahsin Stefan, additional, van Ham, Tjakko J, additional, and Kaya, Namik, additional

Published
2021
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12. BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms

Author

Barish, Scott, primary, Barakat, Tahsin Stefan, additional, Michel, Brittany C., additional, Mashtalir, Nazar, additional, Phillips, Jennifer B., additional, Valencia, Alfredo M., additional, Ugur, Berrak, additional, Wegner, Jeremy, additional, Scott, Tiana M., additional, Bostwick, Brett, additional, Murdock, David R., additional, Dai, Hongzheng, additional, Perenthaler, Elena, additional, Nikoncuk, Anita, additional, van Slegtenhorst, Marjon, additional, Brooks, Alice S., additional, Keren, Boris, additional, Nava, Caroline, additional, Mignot, Cyril, additional, Douglas, Jessica, additional, Rodan, Lance, additional, Nowak, Catherine, additional, Ellard, Sian, additional, Stals, Karen, additional, Lynch, Sally Ann, additional, Faoucher, Marie, additional, Lesca, Gaetan, additional, Edery, Patrick, additional, Engleman, Kendra L., additional, Zhou, Dihong, additional, Thiffault, Isabelle, additional, Herriges, John, additional, Gass, Jennifer, additional, Louie, Raymond J., additional, Stolerman, Elliot, additional, Washington, Camerun, additional, Vetrini, Francesco, additional, Otsubo, Aiko, additional, Pratt, Victoria M., additional, Conboy, Erin, additional, Treat, Kayla, additional, Shannon, Nora, additional, Camacho, Jose, additional, Wakeling, Emma, additional, Yuan, Bo, additional, Chen, Chun-An, additional, Rosenfeld, Jill A., additional, Westerfield, Monte, additional, Wangler, Michael, additional, Yamamoto, Shinya, additional, Kadoch, Cigall, additional, Scott, Daryl A., additional, and Bellen, Hugo J., additional

Published
2020
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14. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author

Perenthaler, Elena, primary, Nikoncuk, Anita, additional, Yousefi, Soheil, additional, Berdowski, Woutje M., additional, Alsagob, Maysoon, additional, Capo, Ivan, additional, van der Linde, Herma C., additional, van den Berg, Paul, additional, Jacobs, Edwin H., additional, Putar, Darija, additional, Ghazvini, Mehrnaz, additional, Aronica, Eleonora, additional, van IJcken, Wilfred F. J., additional, de Valk, Walter G., additional, Medici-van den Herik, Evita, additional, van Slegtenhorst, Marjon, additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Kohler, Jennefer N., additional, Bernstein, Jonathan A., additional, Monaghan, Kristin G., additional, Begtrup, Amber, additional, Torene, Rebecca, additional, Al Futaisi, Amna, additional, Al Murshedi, Fathiya, additional, Mani, Renjith, additional, Al Azri, Faisal, additional, Kamsteeg, Erik-Jan, additional, Mojarrad, Majid, additional, Eslahi, Atieh, additional, Khazaei, Zaynab, additional, Darmiyan, Fateme Massinaei, additional, Doosti, Mohammad, additional, Karimiani, Ehsan Ghayoor, additional, Vandrovcova, Jana, additional, Zafar, Faisal, additional, Rana, Nuzhat, additional, Kandaswamy, Krishna K., additional, Hertecant, Jozef, additional, Bauer, Peter, additional, AlMuhaizea, Mohammed A., additional, Salih, Mustafa A., additional, Aldosary, Mazhor, additional, Almass, Rawan, additional, Al-Quait, Laila, additional, Qubbaj, Wafa, additional, Coskun, Serdar, additional, Alahmadi, Khaled O., additional, Hamad, Muddathir H. A., additional, Alwadaee, Salem, additional, Awartani, Khalid, additional, Dababo, Anas M., additional, Almohanna, Futwan, additional, Colak, Dilek, additional, Dehghani, Mohammadreza, additional, Mehrjardi, Mohammad Yahya Vahidi, additional, Gunel, Murat, additional, Ercan-Sencicek, A. Gulhan, additional, Passi, Gouri Rao, additional, Cheema, Huma Arshad, additional, Efthymiou, Stephanie, additional, Houlden, Henry, additional, Bertoli-Avella, Aida M., additional, Brooks, Alice S., additional, Retterer, Kyle, additional, Maroofian, Reza, additional, Kaya, Namik, additional, van Ham, Tjakko J., additional, and Barakat, Tahsin Stefan, additional

Published
2019
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16. Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy

Author

Groen, EJN, Perenthaler, Elena, Courtney, NL, Jordan, CY, Shorrock, HK, van der Hoorn, D, Huang, YT, Murray, LM, Viero, G, Gillingwater, TH, and Clinical Genetics

Subjects
nervous system, nervous system diseases
Abstract

Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by deleterious variants in SMN1 that lead to a marked decrease in survival motor neuron (SMN) protein expression. Humans have a second SMN gene (SMN2) that is almost identical to SMN1. However, due to alternative splicing the majority of SMN2 messenger ribonucleic acid (mRNA) is translated into a truncated, unstable protein that is quickly degraded. Because the presence of SMN2 provides a unique opportunity for therapy development in SMA patients, the mechanisms that regulate SMN2 splicing and mRNA expression have been elucidated in great detail. In contrast, how much SMN protein is produced at different developmental time points and in different tissues remains under-characterized. In this study, we addressed this issue by determining SMN protein expression levels at three developmental time points across six different mouse tissues and in two distinct mouse models of SMA (‘severe’ Taiwanese and ‘intermediate’ Smn2B/− mice). We found that, in healthy control mice, SMN protein expression was significantly influenced by both age and tissue type. When comparing mouse models of SMA, we found that, despite being transcribed from genetically different alleles, control SMN levels were relatively similar. In contrast, the degree of SMN depletion between tissues in SMA varied substantially over time and between the two models. These findings offer an explanation for the differential vulnerability of tissues and organs observed in SMA and further our understanding of the systemic and temporal requirements for SMN with direct relevance for developing effective therapies for SMA.

Published
2018

17. Functional Dissection of the Enhancer Repertoire in Human Embryonic Stem Cells

Author

Barakat, Tahsin Stefan, Halbritter, Florian, Zhang, Man, Rendeiro, André F., Perenthaler, Elena, Bock, Christoph, Chambers, Ian, and Clinical Genetics

Subjects
NANOG, genome-wide functional enhancer map, naive pluripotency, super-enhancers, H3K4me1, ChIP-STARR-seq, OCT4, transposable elements, H3K27ac
Abstract

Enhancers are genetic elements that regulate spatiotemporal gene expression. Enhancer function requires transcription factor (TF) binding and correlates with histone modifications. However, the extent to which TF binding and histone modifications functionally define active enhancers remains unclear. Here, we combine chromatin immunoprecipitation with a massively parallel reporter assay (ChIP-STARR-seq) to identify functional enhancers in human embryonic stem cells (ESCs) genome-wide in a quantitative unbiased manner. Although active enhancers associate with TFs, only a minority of regions marked by NANOG, OCT4, H3K27ac, and H3K4me1 function as enhancers, with activity markedly changing under naive versus primed culture conditions. We identify an enhancer set associated with functions extending to non-ESC-specific processes. Moreover, although transposable elements associate with putative enhancers, only some exhibit activity. Similarly, within super-enhancers, large tracts are non-functional, with activity restricted to small sub-domains. This catalog of validated enhancers provides a valuable resource for further functional dissection of the regulatory genome.

Published
2018

20. In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology

Author

Bernabò, Paola, Tebaldi, Toma, Groen, Ewout J.N., Lane, Fiona M., Perenthaler, Elena, Mattedi, Francesca, Newbery, Helen J., Zhou, Haiyan, Zuccotti, Paola, Potrich, Valentina, Shorrock, Hannah K., Muntoni, Francesco, Quattrone, Alessandro, Gillingwater, Thomas H., and Viero, Gabriella

Subjects
Motor Neurons, Genetics and Molecular Biology (all), Proteome, neurodegeneration, translatome, motor neuron disease, polysomal profiling, ribosome, SMN, spinal muscular atrophy, Biochemistry, Genetics and Molecular Biology (all), Survival of Motor Neuron 1 Protein, Biochemistry, Article, Muscular Atrophy, Spinal, Mice, lcsh:Biology (General), Polyribosomes, Protein Biosynthesis, Animals, Transcriptome, lcsh:QH301-705.5, Cells, Cultured
Abstract

Summary Genetic alterations impacting ubiquitously expressed proteins involved in RNA metabolism often result in neurodegenerative conditions, with increasing evidence suggesting that translation defects can contribute to disease. Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, whose role in pathogenesis remains unclear. Here, we identified in vivo and in vitro translation defects that are cell autonomous and SMN dependent. By determining in parallel the in vivo transcriptome and translatome in SMA mice, we observed a robust decrease in translation efficiency arising during early stages of disease. We provide a catalogue of RNAs with altered translation efficiency, identifying ribosome biology and translation as central processes affected by SMN depletion. This was further supported by a decrease in the number of ribosomes in SMA motor neurons in vivo. Overall, our findings suggest ribosome biology as an important, yet largely overlooked, factor in motor neuron degeneration., Graphical Abstract, Highlights • Polysomal profiling reveals translation defects in SMA mice • Translation defects are SMN dependent and cell autonomous • Translation efficiency alterations highlight defects in ribosome biology • The number of axonal ribosomes is decreased in SMA in vivo, Bernabò et al. analyzed translation in a mouse model of spinal muscular atrophy and identified translation defects that arise early in pathogenesis, are cell autonomous, and are accompanied by a low number of axonal ribosomes in diseased nerves. Their findings highlight ribosome biology as a central hallmark of the disease.

Published
2017

21. Active Ribosome Profiling with RiboLace

Author

Clamer, Massimiliano, primary, Tebaldi, Toma, additional, Lauria, Fabio, additional, Bernabò, Paola, additional, Gómez-Biagi, Rodolfo F., additional, Marchioretto, Marta, additional, Kandala, Divya T., additional, Minati, Luca, additional, Perenthaler, Elena, additional, Gubert, Daniele, additional, Pasquardini, Laura, additional, Guella, Graziano, additional, Groen, Ewout J.N., additional, Gillingwater, Thomas H., additional, Quattrone, Alessandro, additional, and Viero, Gabriella, additional

Published
2018
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23. In Vivo Translatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology

Author

Bernabò, Paola, primary, Tebaldi, Toma, additional, Groen, Ewout J.N., additional, Lane, Fiona M., additional, Perenthaler, Elena, additional, Mattedi, Francesca, additional, Newbery, Helen J., additional, Zhou, Haiyan, additional, Zuccotti, Paola, additional, Potrich, Valentina, additional, Shorrock, Hannah K., additional, Muntoni, Francesco, additional, Quattrone, Alessandro, additional, Gillingwater, Thomas H., additional, and Viero, Gabriella, additional

Published
2017
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24. Active ribosome profiling with RiboLace

Author

Clamer, Massimiliano, primary, Tebaldi, Toma, additional, Lauria, Fabio, additional, Bernabò, Paola, additional, Gómez-Biagi, Rodolfo F., additional, Perenthaler, Elena, additional, Gubert, Daniele, additional, Pasquardini, Laura, additional, Guella, Graziano, additional, Groen, Ewout J.N., additional, Gillingwater, Thomas H., additional, Quattrone, Alessandro, additional, and Viero, Gabriella, additional

Published
2017
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25. In vivo translatome profiling reveals early defects in ribosome biology underlying SMA pathogenesis

Author

Bernabò, Paola, primary, Tebaldi, Toma, additional, Groen, Ewout JN, additional, Lane, Fiona M, additional, Perenthaler, Elena, additional, Mattedi, Francesca, additional, Newbery, Helen J, additional, Zhou, Haiyan, additional, Zuccotti, Paola, additional, Potrich, Valentina, additional, Muntoni, Francesco, additional, Quattrone, Alessandro, additional, Gillingwater, Thomas H, additional, and Viero, Gabriella, additional

Published
2017
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26. In VivoTranslatome Profiling in Spinal Muscular Atrophy Reveals a Role for SMN Protein in Ribosome Biology

Author

Bernabò, Paola, Tebaldi, Toma, Groen, Ewout J.N., Lane, Fiona M., Perenthaler, Elena, Mattedi, Francesca, Newbery, Helen J., Zhou, Haiyan, Zuccotti, Paola, Potrich, Valentina, Shorrock, Hannah K., Muntoni, Francesco, Quattrone, Alessandro, Gillingwater, Thomas H., and Viero, Gabriella

Abstract

Genetic alterations impacting ubiquitously expressed proteins involved in RNA metabolism often result in neurodegenerative conditions, with increasing evidence suggesting that translation defects can contribute to disease. Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, whose role in pathogenesis remains unclear. Here, we identified in vivoand in vitrotranslation defects that are cell autonomous and SMN dependent. By determining in parallel the in vivotranscriptome and translatome in SMA mice, we observed a robust decrease in translation efficiency arising during early stages of disease. We provide a catalogue of RNAs with altered translation efficiency, identifying ribosome biology and translation as central processes affected by SMN depletion. This was further supported by a decrease in the number of ribosomes in SMA motor neurons in vivo. Overall, our findings suggest ribosome biology as an important, yet largely overlooked, factor in motor neuron degeneration.

Published
2017
Full Text
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27. Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy.

Author

Groen EJN, Perenthaler E, Courtney NL, Jordan CY, Shorrock HK, van der Hoorn D, Huang YT, Murray LM, Viero G, and Gillingwater TH

Subjects
Alternative Splicing genetics, Animals, Disease Models, Animal, Exons, Humans, Mice, Motor Neurons metabolism, Motor Neurons pathology, Muscular Atrophy, Spinal physiopathology, RNA Splicing genetics, Spinal Cord physiopathology, Survival of Motor Neuron 2 Protein genetics, Muscular Atrophy, Spinal genetics, Survival of Motor Neuron 1 Protein genetics
Abstract

Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by deleterious variants in SMN1 that lead to a marked decrease in survival motor neuron (SMN) protein expression. Humans have a second SMN gene (SMN2) that is almost identical to SMN1. However, due to alternative splicing the majority of SMN2 messenger ribonucleic acid (mRNA) is translated into a truncated, unstable protein that is quickly degraded. Because the presence of SMN2 provides a unique opportunity for therapy development in SMA patients, the mechanisms that regulate SMN2 splicing and mRNA expression have been elucidated in great detail. In contrast, how much SMN protein is produced at different developmental time points and in different tissues remains under-characterized. In this study, we addressed this issue by determining SMN protein expression levels at three developmental time points across six different mouse tissues and in two distinct mouse models of SMA ('severe' Taiwanese and 'intermediate' Smn2B/- mice). We found that, in healthy control mice, SMN protein expression was significantly influenced by both age and tissue type. When comparing mouse models of SMA, we found that, despite being transcribed from genetically different alleles, control SMN levels were relatively similar. In contrast, the degree of SMN depletion between tissues in SMA varied substantially over time and between the two models. These findings offer an explanation for the differential vulnerability of tissues and organs observed in SMA and further our understanding of the systemic and temporal requirements for SMN with direct relevance for developing effective therapies for SMA.

Published
2018
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