Loss-of-function mutations in ATP13A2 are associated with three neurodegenerative diseases: a rare form of Parkinson's disease termed Kufor-Rakeb syndrome (KRS), a lysosomal storage disorder termed neuronal ceroid lipofuscinosis (NCL), and a form of hereditary spastic paraplegia (HSP). Furthermore, recent data suggests that heterozygous carriers of mutations in ATP13A2 may confer risk for the development of Parkinson's disease, similar to the association of mutations in glucocerebrosidase (GBA) with both Parkinson's disease and Gaucher's disease, a lysosomal storage disorder. Mutations in ATP13A2 are generally thought to be loss of function; however, the lack of human autopsy tissue has prevented the field from determining the pathological consequences of losing functional ATP13A2. We and others have previously neuropathologically characterized mice completely lacking murine Atp13a2, demonstrating the presence of lipofuscinosis within the brain - a key feature of NCL, one of the diseases to which ATP13A2 mutations have been linked. To determine if loss of one functional Atp13a2 allele can serve as a risk factor for disease, we have now assessed heterozygous Atp13a2 knockout mice for key features of NCL. In this report, we demonstrate that loss of one functional Atp13a2 allele leads to both microgliosis and astrocytosis in multiple brain regions compared to age-matched controls; however, levels of lipofuscin were only modestly elevated in the cortex of heterozygous Atp13a2 knockout mice over controls. This data suggests the possibility that partial loss of ATP13A2 causes inflammatory changes within the brain which appear to be independent of robust lipofuscinosis. This study suggests that heterozygous loss-of-function mutations in ATP13A2 are likely harmful and indicates that glial involvement in the disease process may be an early event that positions the CNS for subsequent disease development.

中文翻译：

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ATP13A2 的部分丢失导致选择性神经胶质增生，与强脂褐质沉积无关。

ATP13A2 的功能丧失突变与三种神经退行性疾病有关：一种称为 Kufor-Rakeb 综合征 (KRS) 的罕见帕金森病、一种称为神经元蜡样脂褐质沉积症 (NCL) 的溶酶体贮积症和一种遗传性痉挛性截瘫。热休克蛋白）。此外，最近的数据表明，ATP13A2 突变的杂合子携带者可能会带来帕金森病的发展风险，类似于葡萄糖脑苷脂酶 (GBA) 突变与帕金森病和戈谢病（一种溶酶体贮积症）的关联。ATP13A2 的突变通常被认为是功能丧失。然而，由于缺乏人体尸检组织，该领域无法确定失去功能性 ATP13A2 的病理后果。我们和其他人以前对完全缺乏小鼠 Atp13a2 的小鼠进行了神经病理学表征，证明了大脑内存在脂褐质沉积症 - NCL 的一个关键特征，这是与 ATP13A2 突变相关的疾病之一。为了确定一个功能性 Atp13a2 等位基因的缺失是否可以作为疾病的危险因素，我们现在已经评估了杂合 Atp13a2 敲除小鼠的 NCL 关键特征。在本报告中，我们证明与年龄匹配的对照组相比，一个功能性 Atp13a2 等位基因的缺失会导致多个大脑区域的小胶质细胞增生和星形胶质细胞增多症。然而，与对照组相比，杂合 Atp13a2 敲除小鼠的皮质中脂褐质水平仅适度升高。该数据表明 ATP13A2 的部分丢失可能导致大脑内的炎症变化，这似乎与严重的脂褐质沉积无关。该研究表明 ATP13A2 中的杂合功能丧失突变可能是有害的，并表明神经胶质参与疾病过程可能是使 CNS 为随后的疾病发展定位的早期事件。