Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models.
Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models.
复制标题
DOI：
10.3389/fneur.2021.681369
复制
发表时间：
2021
影响因子：
3.4
通讯作者：
Kuwahara T
中科院分区：
文献类型：
--
作者：
Abe T;Kuwahara T
以往对遗传性帕金森病（PD）的遗传学研究已经确定了一组致病基因突变，对PD的致病性有很大的影响。此外，针对散发性PD的全基因组关联研究（GWAS）已经提名了越来越多的影响PD易感性的遗传变异。虽然遗传性PD的临床和病理特征与散发性PD的临床和病理特征不同，但α-突触核蛋白和LRRK 2肯定与两种类型的PD相关，LRRK 2突变是常染色体显性PD的最常见原因。另一方面，从GWAS中鉴定出的风险基因中有很大一部分与溶酶体功能相关，这表明溶酶体在PD发病机制中起着关键作用。实验研究表明，溶酶体活性的维持或上调可以防止神经元功能障碍或变性。本文从细胞模型和动物模型的研究结果出发，对参与溶酶体通路的代表性PD基因产物LRRK 2、VPS 35、ATP 13 A2和葡萄糖脑苷脂酶的作用进行综述，并对它们在PD发病机制中的协同作用进行综述。我们还讨论了靶向溶酶体激活作为治疗神经变性的可能策略的未来前景。
Previous genetic studies on hereditary Parkinson's disease (PD) have identified a set of pathogenic gene mutations that have strong impacts on the pathogenicity of PD. In addition, genome-wide association studies (GWAS) targeted to sporadic PD have nominated an increasing number of genetic variants that influence PD susceptibility. Although the clinical and pathological characteristics in hereditary PD are not identical to those in sporadic PD, α-synuclein, and LRRK2 are definitely associated with both types of PD, with LRRK2 mutations being the most frequent cause of autosomal-dominant PD. On the other hand, a significant portion of risk genes identified from GWAS have been associated with lysosomal functions, pointing to a critical role of lysosomes in PD pathogenesis. Experimental studies have suggested that the maintenance or upregulation of lysosomal activity may protect against neuronal dysfunction or degeneration. Here we focus on the roles of representative PD gene products that are implicated in lysosomal pathway, namely LRRK2, VPS35, ATP13A2, and glucocerebrosidase, and provide an overview of their disease-associated functions as well as their cooperative actions in the pathogenesis of PD, based on the evidence from cellular and animal models. We also discuss future perspectives of targeting lysosomal activation as a possible strategy to treat neurodegeneration.
登录
查看更多内容
影响因子：
8.6
作者：
Appel-Cresswell, Silke;Vilarino-Guell, Carles;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
影响因子：
2.3
作者：
Bendikov-Bar, Inna;Maor, Gali;Filocamo, Mirella;Horowitz, Mia
通讯作者：
Horowitz, Mia
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
6.1
作者：
Chu, Yaping;Dodiya, Hemraj;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
影响因子：
--
作者：
Alvarez-Erviti, Lydia;Rodriguez-Oroz, Maria C.;Schapira, Anthony H. V.
通讯作者：
Schapira, Anthony H. V.