Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models

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 1. Discovery of a plasma Parkinson’s Disease biomarker candidate, pS65-Ubiquitin (pUb) 2. Plasma pUb levels correlate with disease status and progression in PD patients. 3. Identification of a potent, brain penetrant PINK1 activator, MTK458 4. MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complex 5. MTK458 drives clearance of α-synuclein pathology and normalizes pUb in in vivo Parkinson’s models ### Competing Interest Statement The following authors are employees of Mitokinin Inc: R.M.C., R.R., D.D., C.W., S.L., A.M., A.L., A.E., C.T., R.Y.K., J.L., S.H., V.R., D.H., V.G., J.P., D.d.R., and N.T.H : The authors at Mitokinin Inc are equity holders in Mitokinin Inc. S.K. and J.S. are employees of AbbVie Inc. J.W.H. is a consultant and founder of Caraway Therapeutics and a founding scientific advisory board member of Interline Therapeutics. J.B. and S.J are employees of X-Chem. Patent number related to this work: WO2020206363A1