MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias

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.

miRNA-182 regulated MTSS1 inhibits proliferation and invasion in Glioma Cells

“…EMT is a process in which epithelial cells acquire stromal characteristics [37]. Due to some physiological or pathological factors, cells lose their polarity, tight intercellular junctions and adhesive connections and acquire interstitial cell morphology and characteristics [38]. In cancer, EMT is associated with tumor development, invasion, metastasis, and treatment resistance [39].…”

MIM-Deficient Mice Exhibit Anatomical Changes in Dendritic Spines, Cortex Volume and Brain Ventricles, and Functional Changes in Motor Coordination and Learning

“…Missing in Metastasis deficiency is clearly associated with motor-coordination and muscle weakness (Figures 2E,F, Saarikangas et al, 2015; Sistig et al, 2017; Brown et al, 2018). Motor skills and muscle weakness could originate from muscle dysfunction, instead of CNS problems.…”

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

“…Treatment of MSST1 mutant mice with the FDA-approved SFK inhibitor dasatinib prevented the SFKdependent firing defects and delayed the ataxia progression in these mice. Interestingly, the reduced MTSS1 protein level and elevated SFK activity was observed in SCA2-127Q transgenic mice [141].…”

“…The Src family of the nonreceptor tyrosine kinases (SFK) is essential for the nervous system homeostasis and may be involved in the neurodegenerative disease. Recent studies have discovered the involvement of the SFK inhibitor Missing-in-metastasis (MTSS1) in SCA molecular pathology [141]. The lack of MTSS1 in mice led to the increased SFK enzyme activity, accompanied by the PC firing dysfunction and, eventually, to PC cell death.…”