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

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.