Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson's disease.
Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson's disease.
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DOI：
10.1016/j.neuroscience.2012.12.018
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发表时间：
2013-03-01
期刊：
影响因子：
3.3
通讯作者：
Moussa CE
中科院分区：
文献类型：
--
作者：
Lonskaya I;Hebron ML;Algarzae NK;Desforges N;Moussa CE
帕金森病（PD）是一种运动障碍疾病，涉及黑质致密部多巴胺能神经元的死亡。帕金是一种常染色体隐性基因，在早发性帕金森病中发生突变。我们研究了帕金和自噬清除在22例非家族性散发性帕金森病患者和15例对照样本的死后黑质纹状体组织中的作用。在散发性帕金森病的黑质纹状体中，帕金不溶且胞质表达改变。帕金不溶性与泛素化蛋白质降解缺失以及自噬体中α - 突触核蛋白和帕金的积累有关，这表明帕金森病存在自噬缺陷。为了测试帕金在介导自噬清除中的作用，我们使用慢病毒基因转移在大鼠纹状体中表达人野生型或突变型帕金（T240R）以及α - 突触核蛋白。慢病毒表达α - 突触核蛋白导致自噬泡的积累，而帕金与α - 突触核蛋白的共表达促进了自噬清除。亚细胞分级分离显示在基因转移模型中自噬体中α - 突触核蛋白和p - Tau的积累，与在帕金森病大脑中观察到的效应相似，但帕金表达导致蛋白质沉积到溶酶体中。然而，帕金功能缺失突变并不影响自噬清除。综上所述，这些数据表明功能性帕金调节自噬体清除，而帕金溶解度降低可能改变散发性帕金森病中的正常自噬。
Parkinson’s disease (PD) is a motor disorder that involves death of dopaminergic neurons in the substantia nigra pars compacta. Parkin is an autosomal recessive gene that is mutated in early onset PD. We investigated the role of parkin and autophagic clearance in postmortem nigrostriatal tissues from 22 non-familial sporadic PD patients and 15 control samples. Parkin was insoluble with altered cytosolic expression in the nigrostriatum of sporadic PD. Parkin insolubility was associated with lack of degradation of ubiquitinated proteins and accumulation of α-Synuclein and parkin in autophagosomes, suggesting autophagic defects in PD. To test parkin’s role in mediating autophagic clearance, we used lentiviral gene transfer to express human wild type or mutant parkin (T240R) with α-Synuclein in the rat striatum. Lentiviral expression of α-Synuclein led to accumulation of autophagic vacuoles, while co-expression of parkin with α-Synuclein facilitated autophagic clearance. Subcellular fractionation showed accumulation of α-Synuclein and p-Tau in autophagosomes in gene transfer models, similar to the effects observed in PD brains, but parkin expression led to protein deposition into lysosomes. However, parkin loss of function mutation did not affect autophagic clearance. Taken together, these data suggest that functional parkin regulates autophagosome clearance, while decreased parkin solubility may alter normal autophagy in sporadic PD.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
4.7
作者：
Ding H;Dolan PJ;Johnson GV
通讯作者：
Johnson GV
影响因子：
3.5
作者：
Cookson, MR;Lockhart, PJ;Farrer, MJ
通讯作者：
Farrer, MJ
影响因子：
3.5
作者：
Burns, Mark P.;Zhang, Lihua;Moussa, Charbel E. -H.
通讯作者：
Moussa, Charbel E. -H.
影响因子：
3.7
作者：
Benner EJ;Banerjee R;Reynolds AD;Sherman S;Pisarev VM;Tsiperson V;Nemachek C;Ciborowski P;Przedborski S;Mosley RL;Gendelman HE
通讯作者：
Gendelman HE