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24 results on '"Switonski, Pawel M."'

2. Altered H3 histone acetylation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7

Author

Switonski, Pawel M, Delaney, Joe R, Bartelt, Luke C, Niu, Chenchen, Ramos-Zapatero, Maria, Spann, Nathanael J, Alaghatta, Akshay, Chen, Toby, Griffin, Emily N, Bapat, Jaidev, Sopher, Bryce L, and La Spada, Albert R

Subjects
Biological Sciences, Genetics, Rare Diseases, Eye Disease and Disorders of Vision, Neurosciences, Brain Disorders, Neurodegenerative, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Acetylation, Animals, Ataxin-7, Cerebellar Diseases, DNA Repair, Female, Histones, Humans, Male, Mice, Neurons, Peptides, Spinocerebellar Ataxias, ChIP-seq, DNA damage, ataxin-7, cerebellum, epigenetic dysregulation, neurodegeneration, polyglutamine, repair, spinocerebellar ataxia, translocation, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein incorporates into STAGA co-activator complex and interferes with transcription by altering histone acetylation. We performed chromatic immunoprecipitation sequencing ChIP-seq on cerebellum from SCA7 mice and observed increased H3K9-promoter acetylation in DNA repair genes, resulting in increased expression. After detecting increased DNA damage in SCA7 cells, mouse primary cerebellar neurons, and patient stem-cell-derived neurons, we documented reduced homology-directed repair (HDR) and single-strand annealing (SSA). To evaluate repair at endogenous DNA in native chromosome context, we modified linear amplification-mediated high-throughput genome-wide translocation sequencing and found that DNA translocations are less frequent in SCA7 models, consistent with decreased HDR and SSA. Altered DNA repair function in SCA7 may predispose the subject to excessive DNA damage, leading to neuron demise and highlights DNA repair as a therapy target.

Published
2021

3. Metabolic and Organelle Morphology Defects in Mice and Human Patients Define Spinocerebellar Ataxia Type 7 as a Mitochondrial Disease

Author

Ward, Jacqueline M, Stoyas, Colleen A, Switonski, Pawel M, Ichou, Farid, Fan, Weiwei, Collins, Brett, Wall, Christopher E, Adanyeguh, Isaac, Niu, Chenchen, Sopher, Bryce L, Kinoshita, Chizuru, Morrison, Richard S, Durr, Alexandra, Muotri, Alysson R, Evans, Ronald M, Mochel, Fanny, and La Spada, Albert R

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Neurodegenerative, Brain Disorders, Neurosciences, Stem Cell Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adipose Tissue, Animals, Ataxin-7, Blood Glucose, Energy Metabolism, Humans, Kynurenine, Metabolomics, Mice, Mitochondria, Mitochondrial Diseases, NAD, Neural Stem Cells, Organelles, Peptides, Phenotype, Purkinje Cells, Reproducibility of Results, Spinocerebellar Ataxias, Trinucleotide Repeat Expansion, Tryptophan, Purkinje cell, ataxin-7, induced pluripotent stem cells, mitochondria, mouse model, nicotinamide adenine dinucleotide, oxidative metabolism, polyglutamine, spinocerebellar ataxia, trinucleotide repeat, Medical Physiology, Biological sciences
Abstract

Spinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7.

Published
2019

4. Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients.

Author

Bartelt, Luke C., Switonski, Pawel M., Adamek, Grażyna, Longo, Fabiana, Carvalho, Juliana, Duvick, Lisa A., Jarrah, Sabrina I., McLoughlin, Hayley S., Scoles, Daniel R., Pulst, Stefan M., Orr, Harry T., Hull, Court, Lowe, Craig B., and La Spada, Albert R.

Subjects
PURKINJE cells, SPINOCEREBELLAR ataxia, LABORATORY mice, RNA sequencing, POLYGLUTAMINE, CEREBELLUM
Abstract

Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias. Editor's summary: Spinocerebellar ataxias (SCAs) are neurodegenerative diseases affecting coordination and movement. Purkinje cells (PCs) are especially vulnerable in SCAs, but their low abundance makes cell type–specific transcriptomic profiling difficult. Using a PC enrichment protocol for snRNA-seq, Bartelt et al. discovered that genes contributing to zebrin-II PC subtype identity were dysregulated in the SCA7-266Q mouse model. Immunohistochemistry revealed a loss of zebrin-II striping in the cerebella of SCA7-266Q mice and mouse models of other SCA subtypes. snRNA-seq on postmortem cerebellar tissue from patients with SCA7 demonstrated zebrin-II dysregulation in molecular layer interneurons. These results suggest that dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across SCAs. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Published
2024
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6. Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias

Author

Bartelt, Luke C., primary, Switonski, Pawel M., additional, Adamek, Grażyna, additional, Carvalho, Juliana, additional, Duvick, Lisa A., additional, Jarrah, Sabrina I., additional, McLoughlin, Hayley S., additional, Scoles, Daniel R., additional, Pulst, Stefan M., additional, Orr, Harry T., additional, Hull, Court, additional, Lowe, Craig B., additional, and La Spada, Albert R., additional

Published
2023
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8. Contributors

Author

Ajjuri, Rami R., primary, Ali, Yousuf, additional, Arena, Giuseppe, additional, Ashizawa, Tetsuo, additional, Auburger, Georg, additional, Bagchi, Devika P., additional, Baldo, Barbara, additional, Baxter, Sally L., additional, Berman, Robert F., additional, Binder, Lester I., additional, Blackstone, Craig, additional, Breda, Carlo, additional, Brotchie, Jonathan M., additional, Burton, Edward A., additional, Calderon, Diany Paola, additional, Caldwell, Guy A., additional, Caldwell, Kim A., additional, Cenci, M. Angela, additional, Chen, Jianmin, additional, Chesselet, Marie-Francoise, additional, Collins-Praino, Lyndsey E., additional, Colosimo, Carlo, additional, Combs, Benjamin, additional, Correa, Mercè, additional, D’Adamo, Maria Cristina, additional, Dai, Helena, additional, Datta, Debkanya, additional, DeAndrade, Mark P., additional, Dietrich, Paula, additional, Dragatsis, Ioannis, additional, Eidelberg, David, additional, El-Khamisy, Sherif F., additional, Evinger, Craig L., additional, Fassier, Coralie, additional, Figiel, Maciej, additional, Fox, Susan H., additional, Francardo, Veronica, additional, Freeman, Amanda A.H., additional, Frucht, Steven, additional, Gardiner, John, additional, Giasson, Benoit, additional, Giorgini, Flaviano, additional, Gispert, Suzana, additional, González-Cabo, Pilar, additional, Gradinaru, Viviana, additional, Hall, Marleshia, additional, Hama, Hiroko, additional, Handforth, Adrian, additional, Hayflick, Susan, additional, Hazan, Jamilé, additional, Hedera, Peter, additional, Heiman, Gary A., additional, Herrup, Karl, additional, Hess, Ellen J., additional, Hickey, Patrick, additional, Himmelstein, Diana S., additional, Hoekstra, Pieter J., additional, Houart, Corinne, additional, Hunsaker, Michael Ryan, additional, Iderberg, Hanna, additional, Jackson-Lewis, Vernic, additional, Jankovic, Joseph, additional, Jinnah, H.A., additional, Joensuu, Tarja, additional, Johnston, Tom M., additional, Josephs, Keith A., additional, Kanaan, Nicholas M., additional, Khodakhah, Kamran, additional, Kim, Kwang-Soo, additional, Klinker, F., additional, Kooner, Gurdeep S., additional, Kopra, Outi, additional, Kotzbauer, Paul T., additional, Kozina, Elena, additional, Krismer, Florian, additional, Krzyzosiak, Wlodzimierz J., additional, Kuruvilla, Korah P., additional, Kuzdas, Daniela, additional, Kyriacou, Charalambos P., additional, Leavitt, Blair R., additional, LeDoux, Mark S., additional, Lehesjoki, Anna-Elina, additional, Lester, Deranda, additional, Lewis, Jada, additional, Li, Jiali, additional, Liebetanz, D., additional, Lindgren, Hanna, additional, Mallucci, Giovanna R., additional, Mann, Amandeep, additional, Margolis, Russell L., additional, Mason, Robert P., additional, Mazarei, Gelareh, additional, McDonald, Michael P., additional, Melki, Judith, additional, Méneret, Aurélie, additional, Moscovich, Mariana, additional, Neuner, Irene, additional, O’Donnell, Janis M., additional, Oleas, Janneth, additional, Ondo, William G., additional, Opal, Puneet, additional, Orr, Harry T., additional, Ozdowski, Emily F., additional, Pandolfo, Massimo, additional, Paschou, Peristera, additional, Pascual, Juan M., additional, Patel, Amar, additional, Patel, Neepa, additional, Peres, João N., additional, Pessia, Mauro, additional, Petersén, Åsa, additional, Petrucci, Simona, additional, Pfeiffer, Ronald F., additional, Phielipp, Nicolás M., additional, Pienaar, Ilse Sanet, additional, Pittenger, Christopher, additional, Plummer, Mark R., additional, Podurgiel, Samantha, additional, Przedborski, Serge, additional, Puschmann, Andreas, additional, Reiter, Lawrence T., additional, Ren, Yan, additional, Renvoisé, Benoît, additional, Rose, Samuel J., additional, Ross, Owen A., additional, Roze, Emmanuel, additional, Ruan, Kai, additional, Rudnicki, Dobrila D., additional, Sahara, Naruhiko, additional, Sako, Wataru, additional, Salamone, John D., additional, Sanyal, Subhabrata, additional, Saunders, Thomas L., additional, Schneider, Susanne A., additional, Schulte, Eva C., additional, Schwartzer, Jared J., additional, Sherwood, Nina T., additional, Sibon, Ody, additional, Smeyne, Richard J., additional, Stacy, Mark, additional, Starr, Philip, additional, Staveley, Brian E., additional, Stefanova, Nadia, additional, Subramony, S.H., additional, Swann, Nicole, additional, Switonski, Pawel M., additional, Szlachcic, Wojciech J., additional, Tai, Kwok-Keung, additional, Tiranti, Valeria, additional, Truong, Daniel D., additional, Tyynismaa, Henna, additional, Uluğ, Aziz M., additional, Valente, Enza M., additional, Van Gerpen, Jay A., additional, Vázquez-Manrique, Rafael P., additional, Vemula, Satya, additional, Vidailhet, Marie, additional, Walker, Ruth H., additional, Ward, Sarah M., additional, Wells, Owen S., additional, Wenning, Gregor K., additional, Willet, Kathleen A., additional, Winkelmann, Juliane, additional, Wszolek, Zbigniew K., additional, Xiao, Jianfeng, additional, Yang, X. William, additional, Ylikallio, Emil, additional, Yokoi, Fumiaki, additional, Yue, Zhenyu, additional, and Zhai, R. Grace, additional

Published
2015
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10. B03 Novel hd mouse models enabling new pathogenic mechanisms discovery

Author

Wozna-Wysocka, Magdalena, primary, Przybyl, Lukasz, additional, Jazurek-Ciesiolka, Magdalena, additional, Switonski, Pawel M, additional, Suszynska-Zajczyk, Joanna, additional, Sobieszczanska, Paula, additional, Wronka, Dorota, additional, Misiorek, Julia O, additional, Figura, Grzegorz, additional, Ciesiolka, Adam, additional, Krzyzosiak, Wlodzimierz J, additional, Figiel, Maciej, additional, and Fiszer, Agnieszka, additional

Published
2021
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15. Nicotinamide Pathway-Dependent Sirt1 Activation Restores Calcium Homeostasis to Achieve Neuroprotection in Spinocerebellar Ataxia Type 7

Author

Stoyas, Colleen A., primary, Bushart, David D., additional, Switonski, Pawel M., additional, Ward, Jacqueline M., additional, Alaghatta, Akshay, additional, Tang, Mi-bo, additional, Niu, Chenchen, additional, Wadhwa, Mandheer, additional, Huang, Haoran, additional, Savchenko, Alex, additional, Gariani, Karim, additional, Xie, Fang, additional, Delaney, Joseph R., additional, Gaasterland, Terry, additional, Auwerx, Johan, additional, Shakkottai, Vikram G., additional, and La Spada, Albert R., additional

Published
2020
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16. FairSubset: A tool to choose representative subsets of data for use with replicates or groups of different sample sizes

Author

Ortell, Katherine K, Switonski, Pawel M, Delaney, Joe R, Ortell, Katherine K, Switonski, Pawel M, and Delaney, Joe R

Abstract

High-impact journals are promoting transparency of data. Modern scientific methods can be automated and produce disparate samples sizes. In many cases, it is desirable to retain identical or pre-defined sample sizes between replicates or groups. However, choosing which subset of originally acquired data that best matches the entirety of the data set without introducing bias is not trivial. Here, we released a free online tool, FairSubset, and its constituent Shiny App R code to subset data in an unbiased fashion. Subsets were set at the same N across samples and retained representative average and standard deviation information. The method can be used for quantitation of entire fields of view or other replicates without biasing the data pool toward large N samples. We showed examples of the tool’s use with fluorescence data and DNA-damage related Comet tail quantitation. This FairSubset tool and the method to retain distribution information at the single-datum level may be considered for standardized use in fair publishing practices.

Published
2019

23. Mouse Ataxin-3 Functional Knock-Out Model

Author

Switonski, Pawel M., primary, Fiszer, Agnieszka, additional, Kazmierska, Katarzyna, additional, Kurpisz, Maciej, additional, Krzyzosiak, Wlodzimierz J., additional, and Figiel, Maciej, additional

Published
2010
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24. Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias.

Author

Bartelt LC, Switonski PM, Adamek G, Carvalho J, Duvick LA, Jarrah SI, McLoughlin HS, Scoles DR, Pulst SM, Orr HT, Hull C, Lowe CB, and La Spada AR

Abstract

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a PC nuclei enrichment protocol and applied it to single-nucleus RNA-seq of a SCA7 knock-in mouse model. Our results unify prior observations into a central mechanism of cell identity loss, impacting both glia and PCs, driving accumulation of inhibitory synapses and altered PC spiking. Zebrin-II subtype dysregulation is the predominant signal in PCs, leading to complete loss of zebrin-II striping at motor symptom onset in SCA7 mice. We show this zebrin-II subtype degradation is shared across Polyglutamine Ataxia mouse models and SCA7 patients. It has been speculated that PC subtype organization is critical for cerebellar function, and our results suggest that a breakdown of zebrin-II parasagittal striping is pathological., Competing Interests: Declarations The authors have nothing to declare.

Published
2023
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