Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia.
Mov Disord. 2015 May;30(6):770-9. doi: 10.1002/mds.26243. Epub 2015 Apr 21.
The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor-Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn(2+) homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α-synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α-synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society.
ATP13A2（PARK9）在帕金森病（PD）中的重要性随着该基因的突变导致 Kufor-Rakeb 综合征的发现而显现出来，这是一种常染色体隐性遗传的少年起病的帕金森综合征，伴有痉挛、核上性眼球运动障碍和痴呆的附加三联征。已经鉴定出 11 个具有纯合或复合杂合 ATP13A2 突变的独立家系。这些报告清楚地表明，该病症表现出相当大的临床异质性，即使在携带相同突变的家庭成员中，疾病也存在明显的表型差异。该蛋白在散发性 PD 中的相关性通过在该组患者中存在单个杂合 ATP13A2 突变以及在患病患者的黑质中该基因的表达改变得到证明。最近已经证明了 ATP13A2 在 Zn（2+）稳态中的参与，这种干扰的分子后果导致溶酶体损伤、α-突触核蛋白积累和线粒体功能障碍。这些发现为 ATP13A2 在 PD 发展中的作用提供了新的认识，并确定了一个治疗靶点，可能改善帕金森病中的α-突触核蛋白积累、溶酶体和线粒体功能障碍。©2015 年国际帕金森病和运动障碍学会。
