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Chemical Inhibition of PTEN‐Induced Kinase 1 (PINK1) Degradation Confers Neuroprotection in Culture Models of Parkinson’s Disease
Author(s) -
Chu Charleen T.,
Liu Yuan,
Verma Manish,
Wang Kent Z. Q.,
Otero P. Anthony,
Chen Bill,
Mallampalli Rama
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01984
Subject(s) - pink1 , neuroprotection , parkin , kinase , pten , parkinson's disease , ubiquitin ligase , proteasome , programmed cell death , microbiology and biotechnology , disease , chemistry , biology , apoptosis , cancer research , pharmacology , medicine , ubiquitin , biochemistry , gene , pi3k/akt/mtor pathway
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. Objective We hypothesized that stabilization of PINK1 by interfering with binding to its SCF ubiquitin ligase complex would elevate PINK1 expression levels and confer neuroprotection. Methods & Results After 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. Conclusions Our 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 Information Grant 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.