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Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder characterized by motor incoordination, mild cognitive decline, respiratory dysfunction, and early lethality. It is caused by the expansion of the polyglutamine (polyQ) tract in Ataxin-1 (ATXN1), which stabilizes the pr...

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Autores principales: Nitschke, Larissa, Coffin, Stephanie L., Xhako, Eder, El-Najjar, Dany B., Orengo, James P., Alcala, Elizabeth, Dai, Yanwan, Wan, Ying-Wooi, Liu, Zhandong, Orr, Harry T., Zoghbi, Huda Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934855/
https://www.ncbi.nlm.nih.gov/pubmed/33554954
http://dx.doi.org/10.1172/jci.insight.144955
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author Nitschke, Larissa
Coffin, Stephanie L.
Xhako, Eder
El-Najjar, Dany B.
Orengo, James P.
Alcala, Elizabeth
Dai, Yanwan
Wan, Ying-Wooi
Liu, Zhandong
Orr, Harry T.
Zoghbi, Huda Y.
author_facet Nitschke, Larissa
Coffin, Stephanie L.
Xhako, Eder
El-Najjar, Dany B.
Orengo, James P.
Alcala, Elizabeth
Dai, Yanwan
Wan, Ying-Wooi
Liu, Zhandong
Orr, Harry T.
Zoghbi, Huda Y.
author_sort Nitschke, Larissa
collection PubMed
description Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder characterized by motor incoordination, mild cognitive decline, respiratory dysfunction, and early lethality. It is caused by the expansion of the polyglutamine (polyQ) tract in Ataxin-1 (ATXN1), which stabilizes the protein, leading to its toxic accumulation in neurons. Previously, we showed that serine 776 (S776) phosphorylation is critical for ATXN1 stability and contributes to its toxicity in cerebellar Purkinje cells. Still, the therapeutic potential of disrupting S776 phosphorylation on noncerebellar SCA1 phenotypes remains unstudied. Here, we report that abolishing S776 phosphorylation specifically on the polyQ-expanded ATXN1 of SCA1-knockin mice reduces ATXN1 throughout the brain and not only rescues the cerebellar motor incoordination but also improves respiratory function and extends survival while not affecting the hippocampal learning and memory deficits. As therapeutic approaches are likely to decrease S776 phosphorylation on polyQ-expanded and WT ATXN1, we further disrupted S776 phosphorylation on both alleles and observed an attenuated rescue, demonstrating a potential protective role of WT allele. This study not only highlights the role of S776 phosphorylation to regulate ATXN1 levels throughout the brain but also suggests distinct brain region–specific disease mechanisms and demonstrates the importance of developing allele-specific therapies for maximal benefits in SCA1.
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spelling pubmed-79348552021-03-09 Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1 Nitschke, Larissa Coffin, Stephanie L. Xhako, Eder El-Najjar, Dany B. Orengo, James P. Alcala, Elizabeth Dai, Yanwan Wan, Ying-Wooi Liu, Zhandong Orr, Harry T. Zoghbi, Huda Y. JCI Insight Research Article Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder characterized by motor incoordination, mild cognitive decline, respiratory dysfunction, and early lethality. It is caused by the expansion of the polyglutamine (polyQ) tract in Ataxin-1 (ATXN1), which stabilizes the protein, leading to its toxic accumulation in neurons. Previously, we showed that serine 776 (S776) phosphorylation is critical for ATXN1 stability and contributes to its toxicity in cerebellar Purkinje cells. Still, the therapeutic potential of disrupting S776 phosphorylation on noncerebellar SCA1 phenotypes remains unstudied. Here, we report that abolishing S776 phosphorylation specifically on the polyQ-expanded ATXN1 of SCA1-knockin mice reduces ATXN1 throughout the brain and not only rescues the cerebellar motor incoordination but also improves respiratory function and extends survival while not affecting the hippocampal learning and memory deficits. As therapeutic approaches are likely to decrease S776 phosphorylation on polyQ-expanded and WT ATXN1, we further disrupted S776 phosphorylation on both alleles and observed an attenuated rescue, demonstrating a potential protective role of WT allele. This study not only highlights the role of S776 phosphorylation to regulate ATXN1 levels throughout the brain but also suggests distinct brain region–specific disease mechanisms and demonstrates the importance of developing allele-specific therapies for maximal benefits in SCA1. American Society for Clinical Investigation 2021-02-08 /pmc/articles/PMC7934855/ /pubmed/33554954 http://dx.doi.org/10.1172/jci.insight.144955 Text en © 2021 Nitschke et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Nitschke, Larissa
Coffin, Stephanie L.
Xhako, Eder
El-Najjar, Dany B.
Orengo, James P.
Alcala, Elizabeth
Dai, Yanwan
Wan, Ying-Wooi
Liu, Zhandong
Orr, Harry T.
Zoghbi, Huda Y.
Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1
title Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1
title_full Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1
title_fullStr Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1
title_full_unstemmed Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1
title_short Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1
title_sort modulation of atxn1 s776 phosphorylation reveals the importance of allele-specific targeting in sca1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934855/
https://www.ncbi.nlm.nih.gov/pubmed/33554954
http://dx.doi.org/10.1172/jci.insight.144955
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