Variants in saposin D domain of prosaposin gene linked to Parkinson's disease
Variants in saposin D domain of prosaposin gene linked to Parkinson's disease
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DOI：
10.1093/brain/awaa064
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发表时间：
2020-04-01
期刊：
影响因子：
14.5
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Oji, Yutaka;Hatano, Taku;Hattori, Nobutaka
最近，溶酶体储存障碍的遗传变异被认为与帕金森病的发病机制有关。在这里，我们发现了丙皂苷(PSAP)的变异，这是一种罕见的导致各种溶酶体储存障碍的基因，与帕金森氏症有关。遗传突变筛查发现3个常染色体显性遗传性帕金森病家系的PSAP皂苷D结构域存在致病突变。全外显子组测序显示，在之前发现的帕金森氏症致病基因或溶酶体储存障碍致病基因中没有其他变异。一项病例对照关联研究发现，散发性帕金森病患者PSAP皂苷D结构域内含子区域的两个变异(rs4747203和rs885828)在日本和台湾的联合队列中具有显著更高的等位基因频率。我们发现在患者来源的皮肤成纤维细胞或诱导的多巴胺多巴胺能神经元中，自噬空泡异常聚集，自噬通量受损，丙皂苷在细胞内的定位改变，以及α-突触核蛋白的聚集。在小鼠中，PSAP皂苷D突变导致进行性运动能力下降和多巴胺能神经变性。我们的数据为PSAP皂苷D结构域参与帕金森病提供了新的遗传学证据。
Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of alpha-synuclein in patientderived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.