Department of Neuroscience, University of Minnesota, 321 Church Street SE, Minneapolis, MN, 55455, USA.
Department of Lab Medicine and Pathology, University of Minnesota, 420 Delaware Street SE, Minneapolis, 55455, USA.
Cerebellum. 2021 Jun;20(3):420-429. doi: 10.1007/s12311-020-01226-3. Epub 2021 Jan 4.
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin1 (ATXN1) gene. SCA1 is characterized by motor deficits, cerebellar neurodegeneration, and gliosis and gene expression changes. Expression of brain-derived neurotrophic factor (BDNF), growth factor important for the survival and function of cerebellar neurons, is decreased in ATXN1[82Q] mice, the Purkinje neuron specific transgenic mouse model of SCA1. As this decrease in BDNF expression may contribute to cerebellar neurodegeneration, we tested whether delivery of extrinsic human BDNF via osmotic ALZET pumps has a beneficial effect on disease severity in this mouse model of SCA1. Additionally, to test the effects of BDNF on established and progressing cerebellar pathogenesis and motor deficits, we delivered BDNF post-symptomatically. We have found that post-symptomatic delivery of extrinsic BDNF ameliorated motor deficits and cerebellar pathology (i.e., dendritic atrophy of Purkinje cells, and astrogliosis) indicating therapeutic potential of BDNF even after the onset of symptoms in SCA1. However, BDNF did not alter Purkinje cell gene expression changes indicating that certain aspects of disease pathogenesis cannot be ameliorated/slowed down with BDNF and that combinational therapies may be needed.
脊髓小脑共济失调 1 型（SCA1）是一种致命的神经退行性疾病，由 Ataxin1（ATXN1）基因中 CAG 重复异常扩增引起。SCA1 的特征是运动功能障碍、小脑神经退行性变、神经胶质增生和基因表达变化。脑源性神经营养因子（BDNF）的表达减少，BDNF 是一种对小脑神经元存活和功能很重要的生长因子，在 ATXN1[82Q]小鼠中，即 SCA1 的浦肯野神经元特异性转基因小鼠模型中减少。由于 BDNF 表达的减少可能导致小脑神经退行性变，我们测试了通过渗透 ALZET 泵给予外源性人 BDNF 是否对这种 SCA1 小鼠模型的疾病严重程度有有益的影响。此外，为了测试 BDNF 对已建立和进展的小脑发病机制和运动功能障碍的影响，我们进行了 BDNF 的症状后给药。我们发现，外源性 BDNF 的症状后给药改善了运动功能障碍和小脑病理（即浦肯野细胞树突萎缩和星形胶质增生），表明 BDNF 即使在 SCA1 症状出现后也具有治疗潜力。然而，BDNF 并未改变浦肯野细胞基因表达变化，这表明某些疾病发病机制方面不能通过 BDNF 得到改善/减缓，可能需要联合治疗。
