A naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.

TitleA naturally occurring variant of SHLP2 is a protective factor in Parkinson's disease.
Publication TypeJournal Article
Year of PublicationForthcoming
AuthorsKim, S-J, Miller, B, Hartel, NG, Ramirez, R, Braniff, RGonzalez, Leelaprachakul, N, Huang, A, Wang, Y, Arpawong, TEm, Crimmins, EM, Wang, P, Sun, X, Liu, C, Levy, D, Yen, K, Petzinger, GM, Graham, NA, Jakowec, MW, Cohen, P
JournalMolecular Psychiatry
ISSN Number1476-5578
KeywordsDNA, Parkinson Disease
Abstract

Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) have been associated with a reduced risk of developing Parkinson's disease (PD), yet the underlying mechanisms remain elusive. In this study, we investigate the functional role of a PD-associated mtSNP that impacts the mitochondrial-derived peptide (MDP) Small Humanin-like Peptide 2 (SHLP2). We identify m.2158 T > C, a mtSNP associated with reduced PD risk, within the small open reading frame encoding SHLP2. This mtSNP results in an alternative form of SHLP2 (lysine 4 replaced with arginine; K4R). Using targeted mass spectrometry, we detect specific tryptic fragments of SHLP2 in neuronal cells and demonstrate its binding to mitochondrial complex 1. Notably, we observe that the K4R variant, associated with reduced PD risk, exhibits increased stability compared to WT SHLP2. Additionally, both WT and K4R SHLP2 show enhanced protection against mitochondrial dysfunction in in vitro experiments and confer protection against a PD-inducing toxin, a mitochondrial complex 1 inhibitor, in a mouse model. This study sheds light on the functional consequences of the m.2158 T > C mtSNP on SHLP2 and provides insights into the potential mechanisms by which this mtSNP may reduce the risk of PD.

DOI10.1038/s41380-023-02344-0
Citation Key13675
PubMed ID38167865
PubMed Central ID9250984
Grant ListR01AG068405 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
P30AG068345 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /
W81XWH2110625 / / U.S. Department of Defense (United States Department of Defense) /