Department of Immunology and Microbiology, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States; Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States.
Palm Beach Gardens, FL 33418, United States.
Neurobiol Dis. 2019 Apr;124:248-262. doi: 10.1016/j.nbd.2018.11.015. Epub 2018 Nov 22.
We recently identified a truncated and phosphorylated form of α-synuclein, pα-syn*, as a key neurotoxic α-synuclein species found in cultured neurons, as well as in mouse and Parkinson's disease patients' brains. Small pα-syn* aggregates localize to mitochondria and induce mitochondrial damage and fragmentation. Herein, we investigated the molecular basis of pα-syn*-induced toxicity. By immunofluorescence, we found phosphorylated MKK4, JNK, ERK5 and p38 MAPKs in pα-syn* inclusions. pJNK colocalized with pα-syn* at mitochondria and mitochondria-associated ER membranes where it was associated with BiP and pACC1, markers for the ER and energy deprivation, respectively. We also found that pα-syn* aggregates are tightly associated with small ptau aggregates of similar size. Pα-syn*/ptau inclusions localized to areas of mitochondrial damage and to mitophagic vesicles, showing their role in mitochondrial toxicity, mitophagy induction and their removal along with damaged mitochondrial fragments. Several MAPKs may act cooperatively to phosphorylate tau, notably JNK, p38 and GSK3β, a non-MAPK that was also found phosphorylated in the vicinity of pα-syn*/ptau aggregates. These results add insight into the mechanisms by which pα-syn* exerts its toxic effects that include the phosphorylation of several kinases of the MAPK pathway, as well as the formation of ptau at the mitochondrial membrane, likely contributing to mitotoxicity. Thus pα-syn* appears to be the trigger of a series of kinase mediated pathogenic events and a link between α-syn pathology and tau, another protein known to aggregate in Parkinson's disease and other synucleinopathies.
我们最近发现了一种截断和磷酸化的α-突触核蛋白形式，即 pα-突触核蛋白*，它是在培养神经元以及在小鼠和帕金森病患者大脑中发现的关键神经毒性α-突触核蛋白物质。小的 pα-突触核蛋白聚集体定位于线粒体，并诱导线粒体损伤和碎片化。在此，我们研究了 pα-突触核蛋白-诱导毒性的分子基础。通过免疫荧光，我们发现磷酸化的 MKK4、JNK、ERK5 和 p38 MAPK 存在于 pα-突触核蛋白包含物中。pJNK 与 pα-突触核蛋白在线粒体和线粒体相关内质网膜上共定位，在那里它与 BiP 和 pACC1 相关，BiP 和 pACC1 分别是内质网和能量剥夺的标志物。我们还发现 pα-突触核蛋白聚集体与大小相似的小 ptau 聚集体紧密相关。pα-突触核蛋白/ptau 包含物定位于线粒体损伤区域和噬线粒体小泡，表明它们在线粒体毒性、诱导噬线粒体作用以及与受损线粒体片段一起清除方面的作用。几种 MAPK 可能协同作用以磷酸化 tau，特别是 JNK、p38 和 GSK3β，一种非 MAPK，也在 pα-突触核蛋白*/ptau 包含物附近被发现磷酸化。这些结果增加了对 pα-突触核蛋白发挥其毒性作用的机制的了解，包括 MAPK 途径的几种激酶的磷酸化，以及在线粒体膜上形成 ptau，可能导致线粒体毒性。因此，pα-突触核蛋白似乎是一系列激酶介导的致病事件的触发因素，也是α-突触核蛋白病理与 tau 之间的联系，tau 是另一种已知在帕金森病和其他突触核蛋白病中聚集的蛋白质。
