Pathology-associated change in levels and localization of SIDT2 in postmortem brains of Parkinson's disease and dementia with Lewy bodies patients
Pathology-associated change in levels and localization of SIDT2 in postmortem brains of Parkinson's disease and dementia with Lewy bodies patients
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DOI：
10.1016/j.neuint.2021.105243
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发表时间：
2021-11-23
影响因子：
4.2
通讯作者：
Kabuta, Tomohiro
中科院分区：
文献类型：
--
作者：
Fujiwara, Yuuki;Kabuta, Chihana;Kabuta, Tomohiro
帕金森病（PD）和路易体痴呆（DLB）是主要的神经退行性疾病，它们在涉及路易体形成的病理学方面有共同点，路易体的主要成分是α-突触核蛋白。溶酶体的异常和功能障碍已被认为在路易体病的发病机制中起关键作用。我们最近发现了一种新的溶酶体降解途径，其中各种大分子，包括α-突触核蛋白，直接输入到溶酶体和降解。在这项研究中，我们分析了PD和DLB患者死后大脑中溶酶体膜蛋白SIDT 2的水平和定位，SIDT 2是该途径中的关键因素。PD和DLB病例的前扣带皮层（ACC）中SIDT 2蛋白的水平显著高于年龄匹配的对照组，但在额下回中未观察到这种差异。SIDT 2的水平还显示出与所有受试者（包括对照）的ACC中的α-突触核蛋白水平的强相关性。在所有检查的PD和DLB病例中，SIDT 2与磷酸化α-突触核蛋白阳性的聚集体共定位，磷酸化α-突触核蛋白是路易体的标志。这些观察结果表明，SIDT 2的水平和定位的变化发生在路易体疾病的病变部位，根据路易体病理学的进展。我们的研究结果为路易体疾病以及其他神经退行性疾病的发病机制提供了机制见解，并可能为改善此类疾病的诊断，预防和治疗干预提供线索。
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are major neurodegenerative disorders that share commonalities in their pathology involving the formation of Lewy bodies, the main component of which is alpha-synuclein protein. Aberrancy and dysfunction in lysosomes have been suggested to play critical roles in the pathogenesis of Lewy body diseases. We recently identified a novel lysosomal degradation pathway in which various macromolecules, including alpha-synuclein protein, are directly imported into lysosomes and degraded. In this study, we analyzed the levels and localization of the lysosomal membrane protein SIDT2, a key factor in this pathway, in the postmortem brains of patients with PD and DLB. The levels of SIDT2 protein were significantly higher in the anterior cingulate cortex (ACC) of both PD and DLB cases than in age-matched control subjects, but this difference was not observed in the inferior frontal gyrus. The levels of SIDT2 also showed a strong correlation with alpha-synuclein levels in the ACC of all subjects, including controls. SIDT2 was colocalized with aggregates positive for phosphorylated alpha-synuclein protein, which is a hallmark of Lewy bodies, in all examined cases of both PD and DLB. These observations suggest that changes in the levels and localization of SIDT2 occur at the lesion site of Lewy body diseases in accordance with the progression of Lewy body pathology. Our findings provide mechanistic insights into the pathogenesis of Lewy body diseases, as well as other neurodegenerative disorders, and may provide clues for improved diagnosis, prevention, and therapeutic intervention for such diseases.