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. 2025 Sep;21(9):e70730.
doi: 10.1002/alz.70730.

PINK1 deficiency permits the development of Lewy body dementia with coexisting Aβ pathology

Tong-Yao Gao  1   2 , Xu-Zheng Wang  3 , Yu-Han Xie  4 , Tong Wang  1 , Yun-Bi Lu  1 , Lu-Long Huang  1 , Cong Chen  1 , Ming Zhang  4 , Xin Ma  4 , Ya-Ling Chen  1 , Fu-Xiang Liang  5 , Zhi-Ling Lou  5 , Jin-Sheng Li  5 , Yi-Fan Yu  5 , Jian-Bin Wu  6 , Xiao-Ru Ma  6 , Hua-Li Wang  4 , Chun Tang  3 , Wei-Ping Zhang  1   7
Affiliations

PINK1 deficiency permits the development of Lewy body dementia with coexisting Aβ pathology

Tong-Yao Gao et al. Alzheimers Dement. 2025 Sep.

Abstract

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.

Keywords: APP/PS1 mouse; Alzheimer's disease; Lewy body; Lewy neurite; PTEN‐induced kinase 1; Parkinson's disease; amyloid beta; dementia with Lewy bodies; phosphorylation; α‐synuclein.

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References

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