About this scholarly article

Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models by Randall M. Chin; Rishi Rakhit; Dara Ditsworth; Chengzhong Wang; Johan Bartholomeus; Song Liu; Akash Mody; Alex Laishu; Andrea Eastes; Chao Tai; Roy Y. Kim; Jessica Li; Steven Hansberry; Saurabh Khasnavis; Victoria Rafalski; Donald Herendeen; Virginia Garda; Jennie Phung; Daniel de Roulet; Alban Ordureau; J. Wade Harper; Shawn Johnstone; Jan Stöhr; Nicholas T. Hertz is a scholarly article available to read on EtoBox.

Summary PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson’s disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD. Highlights Discovery of a plasma Parkinson’s Disease biomarker candidate, pS65-Ubiquitin (pUb) Plasma pUb levels correlate with dis

Author

Randall M. Chin; Rishi Rakhit; Dara Ditsworth; Chengzhong Wang; Johan Bartholomeus; Song Liu; Akash Mody; Alex Laishu; Andrea Eastes; Chao Tai; Roy Y. Kim; Jessica Li; Steven Hansberry; Saurabh Khasnavis; Victoria Rafalski; Donald Herendeen; Virginia Garda; Jennie Phung; Daniel de Roulet; Alban Ordureau; J. Wade Harper; Shawn Johnstone; Jan Stöhr; Nicholas T. Hertz

Publisher

Cold Spring Harbor Laboratory

Published

2023