Psychiatric-Like Impairments in Mouse Models of Spinocerebellar Ataxias

2022 ◽  
Author(s):  
Filip Tichanek
Keyword(s):  
Mouse Models ◽  
Spinocerebellar Ataxias

scholarly journals BIOLOGICAL SCIENCES: Neuroscience, cell biology MTSS1/Src family kinase Dysregulation Underlies Multiple Inherited Ataxias

2018 ◽  
Author(s):  
Alexander S. Brown ◽  
Pratap Meera ◽  
Banu Altindag ◽  
Ravi Chopra ◽  
Emma Perkins ◽  
...  
Keyword(s):  
Cell Death ◽  
Nervous System ◽  
Mouse Models ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Purkinje Neuron ◽  
Purkinje Neurons ◽  
Spinocerebellar Ataxias ◽  
Firing Rates ◽  
Protein Levels

AbstractThe 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 StatementThe 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.

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