MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 52; pp. E12407 - E12416
• Main Authors: Brown, Alexander S., Meera, Pratap, Altindag, Banu, Chopra, Ravi, Perkins, Emma M., Paul, Sharan, Scoles, Daniel R., Tarapore, Eric, Magri, Jessica, Huang, Haoran, Jackson, Mandy, Shakkottai, Vikram G., Otis, Thomas S., Pulst, Stefan M., Atwood, Scott X., Oro, Anthony E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.12.2018
• Series: PNAS Plus
• Subjects: Animal models; Animals; Apoptosis; Ataxia; Ataxia - pathology; Ataxin; Biological Sciences; Cell culture; Cell death; Cytoskeleton; Degeneration; Disease Models, Animal; Gene expression; Homeostasis; Humans; Kinases; Metastases; Mice; Mice, Inbred C57BL; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Mutants; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nervous system; Neurodegeneration; PNAS Plus; Proteins; Proteins - metabolism; Purkinje Cells - physiology; Spinocerebellar ataxia; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - metabolism; Spinocerebellar Ataxias - physiopathology; Spinocerebellar Degenerations - metabolism; Spinocerebellar Degenerations - physiopathology; Src protein; src-Family Kinases - metabolism; Therapeutic applications; Tyrosine; actin cytoskeleton; neurodegeneration; Src kinase; BAR domain proteins; spinocerebellar ataxia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1816177115

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.