RT Journal Article SR Electronic T1 BIOLOGICAL SCIENCES: Neuroscience, cell biology MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias JF bioRxiv FD Cold Spring Harbor Laboratory SP 338046 DO 10.1101/338046 A1 Alexander S. Brown A1 Pratap Meera A1 Banu Altindag A1 Ravi Chopra A1 Emma Perkins A1 Sharan Paul A1 Daniel R. Scoles A1 Eric Tarapore A1 Mandy Jackson A1 Vikram G. Shakkottai A1 Thomas S. Otis A1 Stefan M. Pulst A1 Scott X. Atwood A1 Anthony E. Oro YR 2018 UL http://biorxiv.org/content/early/2018/06/04/338046.abstract AB 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 non-receptor 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 a novel 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 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.Significance Statement The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system function, and may contribute to neurodegeneration. Spinocerebellar ataxias (SCAs) are neurodegenerative diseases where Purkinje neurons fire irregularly and degenerate leading to motor problems. We show that the SFK suppressor Missing-in-Metastasis (MTSS1) is a novel ataxia gene that links multiple SCAs. MTSS1 loss results in increased SFK activity, degenerating Purkinje neurons with low basal firing rates, and cell death. Surprisingly, mouse models for three different SCAs show elevated SFK activity, with SCA1 and SCA2 models displaying dramatically reduced MTSS1 protein levels. Treatment of each SCA model with SFK inhibitor corrects Purkinje basal firing, and delays ataxia progression in MTSS1 mutants. Our results identify a common link among disparate neurodegenerative diseases.