Cvetanovic Marija, Hu Yuan-Shih, Opal Puneet
Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Cerebellum. 2017 Apr;16(2):340-347. doi: 10.1007/s12311-016-0794-9.
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell-based clinical trials.
1型脊髓小脑共济失调（SCA1）是一种常染色体显性遗传的神经退行性疾病，由ataxin-1（ATXN1）蛋白中多聚谷氨酰胺（Q）重复序列的扩增引起。SCA1最初表现为小脑共济失调，随后逐渐发展至累及大脑皮层、海马体和脑干。利用能够反映人类疾病复杂性的SCA1基因敲入小鼠，我们发现成年神经前体细胞（NPCs）的增殖能力显著下降。值得注意的是，在体外，即在周围神经元或神经胶质细胞的变性环境之外，也能观察到NPCs增殖的减少，这表明突变的ATXN1在祖细胞内自主发挥作用，干扰了它们的增殖能力。我们的研究结果表明，受损的成年神经发生导致了该疾病的进行性病理变化，特别是在海马体和大脑皮层等区域，干细胞在这些区域提供神经营养因子并参与成年神经发生。这些发现不仅揭示了该疾病的生物学特性，而且对未来任何基于干细胞的临床试验都具有治疗意义。
