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MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias

Brown, AS; Meera, P; Altindag, B; Chopra, R; Perkins, EM; Paul, S; Scoles, DR; ... Oro, AE; + view all (2018) MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias. Proceedings of the National Academy of Sciences of The United States of America , 115 (52) E12407-E12416. 10.1073/pnas.1816177115. Green open access

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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.

Type: Article
Title: MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1816177115
Publisher version: https://doi.org/10.1073/pnas.1816177115
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: BAR domain proteins, Src kinase, actin cytoskeleton, neurodegeneration, spinocerebellar ataxia
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > The Sainsbury Wellcome Centre
URI: https://discovery.ucl.ac.uk/id/eprint/10064963
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