MTSS1/Src Family Kinase Dysregulation Underlies Multiple Inherited Ataxias
Alexander S. Brown1, Pratap Meera2, Banu Altindag1, Ravi Chopra3, Emma Perkins4, Sharan Paul5, Daniel R. Scoles5, Eric Tarapore7, Mandy Jackson4, Vikram G. Shakkottai3,Thomas S. Otis6, Stefan M. Pulst5, Scott X. Atwood1,7,8, Anthony E. Oro1,8
1Program in Epithelial Biology, Stanford University School of Medicine Stanford, CA 94305; 2Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA; 3Department of Neurology, University of Michigan, Ann Arbor, MI; 4Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom; 5Department of Neurology, University of Utah, Salt Lake City, UT; 6Sainsbury Wellcome Centre for Neural Circuits and Behavior, University College London, London, United Kingdom; 7Department of Developmental and Cell Biology, University of California, Irvine
Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of diseases that frequently display Purkinje neuron dysfunction and degeneration leading to motor defects, yet it remains elusive how the many SCA genes interact leading to this common pathological outcome. Src family kinases (SFK) play essential roles in neurodevelopment and circuit function, while being implicated in neurodegenerative disease. Here we reveal that Missing-in-Metastasis (MTSS1), an I-BAR protein and SFK suppressor, is a novel ataxia locus. Loss of MTSS1 results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by neural autophagy and cell death. We also find that known SCA genes ATXN1 (SCA1), ATXN2 (SCA2), and SPTBN2 (SCA5) restrain SFK activity. SCA1, SCA2, and SCA5 mouse models all show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels. Each of these ataxias show slowed Purkinje neuron basal firing rates in mice, an endophenotype corrected by a clinically-approved Src inhibitor. Further, MTSS1 mice treated with Src inhibitors display delayed neurological dysfunction. Our results demonstrate a key role for the evolutionarily conserved MTSS1/SFK network in Purkinje neuron survival and ataxia progression and identify a common therapeutic target.