MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias

Alexander S. Brown, Pratap Meera, Banu Altindag, Ravi Chopra, Emma M. Perkins, Sharan Paul, Daniel R. Scoles, Eric Tarapore, Jessica Magri, Haoran Huang, Mandy Jackson, Vikram G. Shakkottai, Thomas S. Otis, Stefan M. Pulst, Scott X. Atwood, Anthony E. Oro

Research output: Contribution to journalArticlepeer-review

Abstract

The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.

Original languageEnglish (US)
Pages (from-to)E12407-E12416
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number52
DOIs
StatePublished - Dec 26 2018
Externally publishedYes

Keywords

  • Actin cytoskeleton
  • BAR domain proteins
  • Neurodegeneration
  • Spinocerebellar ataxia
  • Src kinase

ASJC Scopus subject areas

  • General

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