Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
PINK1 deficiency permits the development of Lewy body dementia with coexisting Aβ pathology.
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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
Аннотация
INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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.
DISCUSSION: 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.
HIGHLIGHTS: 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.
METHODS: 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.
RESULTS: 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.
DISCUSSION: 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.
HIGHLIGHTS: 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.