Dual targeting of brain region-specific kinases potentiates neurological rescue in Spinocerebellar ataxia type 1

Won Seok Lee, Laura Lavery, Maxime W.C. Rousseaux, Eric B. Rutledge, Youjin Jang, Ying Wooi Wan, Sih Rong Wu, Wonho Kim, Ismael Al-Ramahi, Smruti Rath, Carolyn J. Adamski, Vitaliy V. Bondar, Ambika Tewari, Shirin Soleimani, Samantha Mota, Hari K. Yalamanchili, Harry T. Orr, Zhandong Liu, Juan Botas, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

Abstract

A critical question in neurodegeneration is why the accumulation of disease-driving proteins causes selective neuronal loss despite their brain-wide expression. In Spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded Ataxin-1 (ATXN1) causes selective degeneration of cerebellar and brainstem neurons. Previous studies revealed that inhibiting Msk1 reduces phosphorylation of ATXN1 at S776 as well as its levels leading to improved cerebellar function. However, there are no regulators that modulate ATXN1 in the brainstem—the brain region whose pathology is most closely linked to premature death. To identify new regulators of ATXN1, we performed genetic screens and identified a transcription factor-kinase axis (ZBTB7B-RSK3) that regulates ATXN1 levels. Unlike MSK1, RSK3 is highly expressed in the human and mouse brainstems where it regulates Atxn1 by phosphorylating S776. Reducing Rsk3 rescues brainstem-associated pathologies and deficits, and lowering Rsk3 and Msk1 together improves cerebellar and brainstem function in an SCA1 mouse model. Our results demonstrate that selective vulnerability of brain regions in SCA1 is governed by region-specific regulators of ATXN1, and targeting multiple regulators could rescue multiple degenerating brain areas.

Original languageEnglish (US)
Article numbere106106
JournalEMBO Journal
Volume40
Issue number7
DOIs
StatePublished - Apr 1 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Keywords

  • Ataxin-1
  • MSK1
  • RSK3
  • Spinocerebellar ataxia type 1
  • selective vulnerability

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