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

Larissa Nitschke, Stephanie L. Coffin, Eder Xhako, Dany B. El-Najjar, James P. Orengo, Elizabeth Alcala, Yanwan Dai, Ying Wooi Wan, Zhandong Liu, Harry T. Orr, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Article numbere144955
JournalJCI Insight
Issue number3
StatePublished - Feb 8 2021

Bibliographical note

Funding Information:
We thank Andrea Ballabio and Alessia Calcagni for equipment access, Surabi Veeraragavan for advice on behavioral tests, and Sameer Bajikar, Jennifer Johnson, Ambika Tewari, Niculin Herz, and Manar Zaghlula for their critical comments on the manuscript. We further thank the Genetically Engineered Mouse Core, RNA In Situ Hybridization Core, Cell and Tissue Pathogenesis Core, and the Behavioral Core at Baylor College of Medicine. This work was funded by National Institute of Neurological Disorders and Stroke/NIH grant 4R37NS027699 (HYZ), the Howard Hughes Medical Institute (HYZ), UCB Pharma Union Chimique Belge (HYZ), Baylor Research Advocates for Student Scientists (LN), National Institute of Neurological Disorders and Stroke/NIH grant R01-NS045667 (HTO), the NIH grant P30CA125123 (Genetically Engineered Mouse Core), NIH Shared Instrumentation grant 1S10OD016167 (In Situ Hybridization Core), and the Intellectual and Developmental Disabilities Research Center at Baylor College of Medicine grants U54HD083092, U54HD083092-05S1, and P50HD103555 (Administrative, In Situ Hybridization, Cell and Tissue Pathogenesis, and Behavioral Cores) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH. This content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the NIH.

Publisher Copyright:
© 2021, Nitschke et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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