Department of Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America.
Institute for Translational Neuroscience, University of Minnesota, 2101 6th Street SE, Minneapolis, MN 55455, United States of America; Department of Lab Medicine and Pathology, United States of America.
Neurobiol Dis. 2023 Mar;178:106023. doi: 10.1016/j.nbd.2023.106023. Epub 2023 Jan 29.
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset, dominantly inherited neurodegenerative disease caused by the expanded polyQ tract in the protein ATAXIN1 (ATXN1) and characterized by progressive motor and cognitive impairments. There are no disease-modifying treatments or cures for SCA1. Brain-derived neurotrophic factor (BDNF) plays important role in cerebellar physiology and has shown therapeutic potential for cerebellar pathology in the transgenic mouse model of SCA1, ATXN1[82Q] line that overexpress mutant ATXN1 under a cerebellar Purkinje-cell-specific promoter. Here we demonstrate decreased expression of brain derived neurotrophic factor (BDNF) in the cerebellum and medulla of patients with SCA1. Early stages of disease seem most amenable to therapy. Thus, we next quantified Bdnf expression in Atxn1 mice, a knock-in mouse model of SCA1, during the early symptomatic disease stage in four clinically relevant brain regions: cerebellum, medulla, hippocampus and motor cortex. We found that during the early stages of disease, Bdnf mRNA expression is reduced in the hippocampus and cerebellum, while it is increased in the cortex and brainstem. Importantly, we observed that pharmacological delivery of recombinant BDNF improved motor and cognitive performance, and mitigated pathology in the cerebellum and hippocampus of Atxn1 mice. Our findings demonstrate brain-region specific deficiency of BDNF in SCA1 and show that reversal of low BDNF levels offers the potential for meaningful treatment of motor and cognitive deficits in SCA1.
脊髓小脑共济失调 1 型（SCA1）是一种成年起病、显性遗传的神经退行性疾病，由蛋白 ATAXIN1（ATXN1）中扩展的多聚 Q 区引起，并以进行性运动和认知障碍为特征。目前尚无针对 SCA1 的疾病修正治疗或治愈方法。脑源性神经营养因子（BDNF）在小脑生理学中起着重要作用，并在 SCA1 的转基因小鼠模型 ATXN1[82Q]系中显示出对小脑病理学的治疗潜力，该模型在小脑浦肯野细胞特异性启动子下过表达突变型 ATXN1。在这里，我们证明了 SCA1 患者小脑和延髓中脑源性神经营养因子（BDNF）的表达降低。疾病的早期阶段似乎最适合治疗。因此，我们接下来在 Atxn1 小鼠中定量了 Bdnf 表达，Atxn1 小鼠是 SCA1 的敲入小鼠模型，在四个临床相关脑区：小脑、延髓、海马体和运动皮层的早期症状疾病阶段。我们发现，在疾病的早期阶段，BDNF mRNA 在海马体和小脑中的表达减少，而在皮层和脑干中的表达增加。重要的是，我们观察到重组 BDNF 的药理学传递改善了 Atxn1 小鼠的运动和认知表现，并减轻了小脑和海马体的病理学。我们的研究结果表明 SCA1 中存在脑区特异性 BDNF 缺乏，并表明逆转低 BDNF 水平为 SCA1 的运动和认知缺陷提供了有意义的治疗潜力。
