Gao Tong-Yao, Wang Xu-Zheng, Xie Yu-Han, Wang Tong, Lu Yun-Bi, Huang Lu-Long, Chen Cong, Zhang Ming, Ma Xin, Chen Ya-Ling, Liang Fu-Xiang, Lou Zhi-Ling, Li Jin-Sheng, Yu Yi-Fan, Wu Jian-Bin, Ma Xiao-Ru, Wang Hua-Li, Tang Chun, Zhang Wei-Ping
Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Key Laboratory of Drug Prevention and Control Technology, The Department of Criminal Science and Technology, Zhejiang Police College, Hangzhou, China.
Alzheimers Dement. 2025 Sep;21(9):e70730. doi: 10.1002/alz.70730.
Dementia with Lewy bodies (DLB), a prevalent neurodegenerative dementia, involves α-synuclein (α-syn) aggregates and frequent amyloid beta (Aβ) co-pathology, but mechanistic drivers remain unclear.
We crossed pink1 knockout with APP/PS1 mice, and assessed behavioral and pathological phenotypes of the resulting animals. We also performed biochemical and biophysical characterizations of PTEN-induced kinase 1 (PINK1) phosphorylation of α-syn.
DLB brains show PINK1 deficiency alongside α-syn and Aβ co-pathology. Mirroring human DLB patients, APP/PS1::pink1-/- mice spontaneously develop Lewy pathology at endogenous α-syn levels, affecting both central and peripheral nervous systems with heterogeneous phenotypes. Mechanistically, PINK1 phosphorylates α-syn at Thr44, suppressing Aβ-induced α-syn aggregation. Moreover, pT44-α-syn levels are correlated with PINK1 expression and activity in human brains.
PINK1 deficiency synergizes with Aβ to promote Lewy pathology via loss of protective α-syn phosphorylation. The APP/PS1::pink1-/- model recapitulates key DLB features without α-syn overexpression, offering a valuable tool for future mechanistic and therapeutic studies.
PTEN-induced kinase 1 (PINK1) deficiency, either through reduced expression or impaired activity, is found in human dementia with Lewy bodies (DLB) patients with amyloid beta (Aβ) co-pathology. PINK1 specifically phosphorylates α-synuclein at Thr44, inhibiting Aβ-induced aggregation and preventing the development of Lewy pathology. The APP/PS1::pink1-/- mouse model recapitulates key features of human DLB, exhibiting widespread Lewy pathology and heterogeneous phenotypes. PINK1 alterations emerge as a novel genetic risk factor for DLB, opening new avenues for diagnosis and therapeutic intervention.
路易体痴呆（DLB）是一种常见的神经退行性痴呆，涉及α-突触核蛋白（α-syn）聚集和频繁的淀粉样β蛋白（Aβ）共病理改变，但其机制驱动因素仍不清楚。
我们将pink1基因敲除小鼠与APP/PS1小鼠杂交，并评估所得动物的行为和病理表型。我们还对PTEN诱导激酶1（PINK1）介导的α-syn磷酸化进行了生化和生物物理特性分析。
DLB脑显示PINK1缺乏以及α-syn和Aβ共病理改变。与人类DLB患者相似，APP/PS1::pink1-/-小鼠在内源性α-syn水平下自发出现路易体病理改变，影响中枢和外周神经系统，表现出异质性表型。机制上，PINK1在苏氨酸44位点磷酸化α-syn，抑制Aβ诱导的α-syn聚集。此外，pT44-α-syn水平与人类大脑中的PINK1表达和活性相关。
PINK1缺乏与Aβ协同作用，通过保护性α-syn磷酸化的丧失促进路易体病理改变。APP/PS1::pink1-/-模型在没有α-syn过表达的情况下重现了关键的DLB特征，为未来的机制和治疗研究提供了有价值的工具。
在伴有淀粉样β蛋白（Aβ）共病理改变的人类路易体痴呆（DLB）患者中发现，PTEN诱导激酶1（PINK1）缺乏，原因是表达降低或活性受损。PINK1特异性地在苏氨酸44位点磷酸化α-突触核蛋白，抑制Aβ诱导的聚集并防止路易体病理改变的发展。APP/PS1::pink1-/-小鼠模型重现了人类DLB的关键特征，表现出广泛的路易体病理改变和异质性表型。PINK1改变成为DLB的一种新的遗传危险因素，为诊断和治疗干预开辟了新途径。
