Asher M, Johnson A, Zecevic B, Pease D, Cvetanovic M
Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States.
Department of Neuroscience, Institute for Translational Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States.
Neuroscience. 2016 May 13;322:54-65. doi: 10.1016/j.neuroscience.2016.02.011. Epub 2016 Feb 11.
Polyglutamine expansion in the protein ATAXIN-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), an inherited neurodegenerative disease characterized by motor deficits, cognitive impairment and depression. Although ubiquitously expressed, mutant ATXN1 causes neurodegeneration primarily in the cerebellum, which is responsible for the observed motor deficits. The role of ATXN1 outside of the cerebellum and the causes of cognitive deficits and depression in SCA1 are less understood. In this study, we demonstrate a novel role of ATXN1 in the hippocampus as a regulator of adult neurogenesis. Adult hippocampal neurogenesis is the process of generating new hippocampal neurons and is linked to cognition and mood. We found that loss of ATXN1 causes a decrease in hippocampal neurogenesis in ATXN1 null (Atxn1(-/-)) mice. This decrease was caused by reduced proliferation of neural precursors in the hippocampus of Atxn1(-/-) mice, and persisted even when Atxn1(-/-) hippocampal neural precursors were removed from their natural environment and grown in vitro, suggesting that ATXN1 affects proliferation in a cell-autonomous manner. Moreover, expression of ATXN1 with a pathological polyglutamine (polyQ) expansion in wild-type neural precursor cells inhibited their proliferation. Our data establish a novel role for ATXN1 in the hippocampus as an intrinsic regulator of precursor cell proliferation, and suggest a mechanism by which polyQ expansion and loss of ATXN1 affect hippocampal function, potentially contributing to cognitive deficits and depression. These results indicate that while depletion of ATXN1 is a promising therapeutic approach to treat the cerebellar aspects of SCA1, this approach should be employed with caution given the potential for side effects on hippocampal function with loss of wild-type ATXN1.
蛋白质ataxin-1（ATXN1）中的聚谷氨酰胺扩增会导致1型脊髓小脑共济失调（SCA1），这是一种遗传性神经退行性疾病，其特征为运动功能障碍、认知障碍和抑郁。尽管ATXN1在全身广泛表达，但突变的ATXN1主要在小脑导致神经退行性变，这也是出现所观察到的运动功能障碍的原因。ATXN1在小脑之外的作用以及SCA1中认知缺陷和抑郁的原因尚不太清楚。在本研究中，我们证明了ATXN1在海马体中作为成年神经发生调节因子的新作用。成年海马体神经发生是产生新的海马体神经元的过程，并且与认知和情绪有关。我们发现，在ATXN1基因敲除（Atxn1(-/-)）小鼠中，ATXN1的缺失会导致海马体神经发生减少。这种减少是由Atxn1(-/-)小鼠海马体中神经前体细胞增殖减少引起的，并且即使将Atxn1(-/-)海马体神经前体细胞从其自然环境中取出并在体外培养时，这种减少仍然存在，这表明ATXN1以细胞自主方式影响增殖。此外，在野生型神经前体细胞中具有病理性聚谷氨酰胺（polyQ）扩增的ATXN1表达会抑制它们的增殖。我们的数据确立了ATXN1在海马体中作为前体细胞增殖内在调节因子的新作用，并提出了一种机制，通过该机制聚Q扩增和ATXN1的缺失影响海马体功能，可能导致认知缺陷和抑郁。这些结果表明，虽然ATXN1的缺失是治疗SCA1小脑方面的一种有前景的治疗方法，但鉴于野生型ATXN1缺失可能对海马体功能产生副作用，应谨慎采用这种方法。
