Enhanced Susceptibility of PINK1 Knockout Rats to α-Synuclein Fibrils.
Enhanced Susceptibility of PINK1 Knockout Rats to α-Synuclein Fibrils.
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DOI：
10.1016/j.neuroscience.2020.04.032
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发表时间：
2020-06-15
期刊：
影响因子：
3.3
通讯作者：
Goldberg MS
中科院分区：
文献类型：
--
作者：
Creed RB;Goldberg MS
帕金森病（PD）的主要神经病理学标志是黑质中多巴胺能神经元的丢失和神经元内蛋白聚集体对丝氨酸129（pS129）磷酸化的α-突触核蛋白具有免疫反应性。大多数PD病例是特发性的;然而，在与家族性PD相关的几个基因中已经发现了基因突变。编码α-突触核蛋白的基因突变与显性遗传形式的PD存在因果关系，而PTEN诱导的激酶-1（PINK 1）基因突变与隐性遗传形式的PD存在因果关系。由于异常的α-突触核蛋白聚集体自发出现在PINK 1敲除（KO）大鼠中，我们假设PINK 1缺陷导致内源性α-突触核蛋白更容易聚集。α-突触核蛋白聚集通常不会在小鼠或大鼠中发生，但是，可以通过颅内注射α-突触核蛋白预形成的原纤维（PFF）诱导，这也会诱导注射后3-6个月多巴胺能黑质神经元的损失。由于PINK 1缺陷与早发性PD有关，我们进一步假设PINK 1 KO大鼠与野生型（WT）大鼠相比将显示出更早的PFF诱导的神经变性。在此，我们报告称，与WT同窝对照组相比，将α-突触核蛋白PFF颅内注射到背侧纹状体可诱导PINK 1 KO大鼠大脑中更丰富的pS129 α-突触核蛋白。此外，与注射PFF的WT同窝仔相比，从注射PFF的PINK 1 KO大鼠脑中提取的突触核蛋白更难溶解，表明PINK 1 KO大鼠中α-突触核蛋白病理学进展更大。注射后四周，PFF导致PINK 1 KO大鼠黑质中多巴胺能神经元的显著损失，但WT对照组没有。总之，我们的结果表明，PINK 1缺陷会增加体内对α-突触核蛋白聚集和多巴胺能神经变性的易感性。
The main neuropathological hallmarks of Parkinson’s disease (PD) are loss of dopaminergic neurons in the substantia nigra and intraneuronal protein aggregates immunoreactive for α-synuclein phosphorylated at serine 129 (pS129). Most cases of PD are idiopathic; however, genetic mutations have been identified in several genes linked to familial PD. Mutations in the gene encoding α-synuclein are causally linked to dominantly inherited forms of PD and mutations in the PTEN-induced kinase-1 (PINK1) gene are linked to recessively inherited forms of PD. Because abnormal α-synuclein protein aggregates appear spontaneously in PINK1 knockout (KO) rats, we hypothesize that PINK1-deficiency causes endogenous α-synuclein to be more prone to aggregation. α-Synuclein aggregation does not normally occur in mice or rats, however, it can be induced by intracranial injection of α-synuclein pre-formed fibrils (PFFs), which also induces loss of dopaminergic nigral neurons 3-6 months post-injection. Because PINK1-deficiency is linked to early-onset PD, we further hypothesize that PINK1 KO rats will show earlier PFF-induced neurodegeneration compared to wild-type (WT) rats. Herein, we report that intracranial injection of α-synuclein PFFs into the dorsal striatum induced more abundant pS129 α-synuclein in PINK1 KO rat brains compared to WT littermate controls. Moreover, the synuclein extracted from the brains of PFF-injected PINK1 KO rats was more insoluble compared to PFF-injected WT littermates, suggesting greater progression of α-synuclein pathology in PINK1 KO rats. Four weeks post-injection, PFFs caused significant loss of dopaminergic neurons in the substantia nigra of PINK1 KO rats, but not WT controls. Together, our results indicate that PINK1 deficiency increases vulnerability to α-synuclein aggregation and dopaminergic neurodegeneration in vivo.
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α-突触核蛋白与TOM20结合，并抑制在帕金森氏病中进口的线粒体蛋白。
影响因子：
17.1
作者：
Di Maio R;Barrett PJ;Hoffman EK;Barrett CW;Zharikov A;Borah A;Hu X;McCoy J;Chu CT;Burton EA;Hastings TG;Greenamyre JT
通讯作者：
Greenamyre JT
DOI：
10.1002/mds.27296
发表时间：
2018-05
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
--
作者：
Creed RB;Goldberg MS
通讯作者：
Goldberg MS
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
影响因子：
4.8
作者：
Daher, Joao P. L.;Abdelmotilib, Hisham A.;West, Andrew B.
通讯作者：
West, Andrew B.
影响因子：
4.8
作者：
Froula, Jessica M.;Castellana-Cruz, Marta;Volpicelli-Daley, Laura A.
通讯作者：
Volpicelli-Daley, Laura A.