Chemical Inhibition of PTEN‐Induced Kinase 1 (PINK1) Degradation Confers Neuroprotection in Culture Models of Parkinson’s Disease

Abstract

PTEN‐induced kinase 1 (PINK1) loss of function is linked to familial recessive Parkinson’s disease and, more recently, sporadic Alzheimer’s disease. After mitochondrial processing and release, PINK1 is rapidly degraded by the proteasome.ObjectiveWe hypothesized that stabilization of PINK1 by interfering with binding to its SCF ubiquitin ligase complex would elevate PINK1 expression levels and confer neuroprotection.Methods & ResultsAfter identifying an F‐box protein that interacted with PINK1 and regulated PINK1 expression levels, we used computational binding simulations to screen compounds likely to interfere with this interaction. We identified a small molecule that stabilized PINK1 expression and reduced both cell death and dendritic retraction in several models of Parkinsonian injury in primary cortical neurons and patient‐derived cells.ConclusionsOur identification of an F‐box protein‐targeted small molecule antagonist capable of elevating endogenous PINK1 levels sets the stage for additional target validation for the potential treatment of neurodegenerative diseases and other disorders characterized by mitochondrial dysfunction.Support or Funding InformationGrant support: NIH grants AG026389, NS101628 (co‐funded by NINDS/NIA) and NS065789 (C.T.C.), HL096376, HL097376, HL098174, HL081784, P01 HL114453 and Merit Review Award from the United States Department of Veterans Affairs (R. K. M.), HL139860 and HL133184 (B.B.C.), HL142777 and AHA 16SDG27650008 (Y.L.). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.