2. Academic Validation
  3. PINK1 deficiency permits the development of Lewy body dementia with coexisting Aβ pathology

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

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

Affiliations

  • 1 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Zhejiang Key Laboratory of Drug Prevention and Control Technology, The Department of Criminal Science and Technology, Zhejiang Police College, Hangzhou, China.
  • 3 Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, & Center for Quantitative Biology, PKU-THU Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 4 Beijing Dementia Key Lab, Peking University Institute of Mental Health (Sixth Hospital), National Clinical Research Center for Mental Disorders, NHC Key Laboratory of Mental Health, Peking University, Beijing, China.
  • 5 Department of Thoracic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 6 Department of Human Anatomy, Histology and Embryology, System Medicine Research Center, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Zhejiang Provincial Key Laboratory of Precision Psychiatry, Zhejiang University School of Medicine, Hangzhou, China.
PMID: 40990068 DOI: 10.1002/alz.70730
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.

Figures
Products