MTSS1/Src Family Kinase Dysregulation Underlies Multiple Inherited Ataxias

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Dec 12

PMID 30530649

Citations 11

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

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