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MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias [Neuroscience]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2018-12-26 , DOI: 10.1073/pnas.1816177115
Alexander S. Brown 1 , Pratap Meera 2 , Banu Altindag 1 , Ravi Chopra 3 , Emma M. Perkins 4 , Sharan Paul 5 , Daniel R. Scoles 5 , Eric Tarapore 6 , Jessica Magri 1 , Haoran Huang 3 , Mandy Jackson 4 , Vikram G. Shakkottai 3 , Thomas S. Otis 7 , Stefan M. Pulst 5 , Scott X. Atwood 1, 6 , Anthony E. Oro 1
Affiliation  

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.



中文翻译:

MTSS1 / Src家族激酶失调是多种遗传性共济失调的基础[神经科学]

遗传异质性脊髓小脑共济失调(SCAs)是由浦肯野神经元功能障碍和变性引起的,但其潜在的病理机制仍然难以捉摸。非受体酪氨酸激酶(SFK)的Src家族对于神经系统稳态至关重要,并且越来越多地涉及退行性疾病。在这里,我们揭示了SFK抑制器转移缺失(MTSS1)是一个共济失调基因座,它链接了多个SCA。MTSS1丢失导致SFK活性增加,浦肯野神经元乔化减少,基础放电率降低,继而导致细胞死亡。令人惊讶的是,针对SCA1,SCA2和SCA5的小鼠模型显示出较高的SFK活性,而SCA1和SCA2分别通过降低的基因表达和蛋白质翻译而显着降低了MTSS1蛋白质水平。用临床认可的Src抑制剂治疗每个SCA模型,可纠正Purkinje神经元基础放电,并延迟MTSS1突变体的共济失调进展。我们的结果确定了一个常见的SCA治疗目标,并证明了MTSS1 / SFK在浦肯野神经元存活和共济失调进展中的关键作用。

更新日期:2018-12-28
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