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

Su-Jeong Kim; Brendan Miller; Nicolas G Hartel; Ricardo Ramirez 2nd; Regina Gonzalez Braniff; Naphada Leelaprachakul; Amy Huang; Yuzhu Wang; Thalida Em Arpawong; Eileen M Crimmins; Penglong Wang; Xianbang Sun; Chunyu Liu; Daniel Levy; Kelvin Yen; Giselle M Petzinger; Nicholas A Graham; Michael W Jakowec; Pinchas Cohen

doi:10.1038/s41380-023-02344-0

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

Mol Psychiatry. 2024 Jan 3. doi: 10.1038/s41380-023-02344-0. Online ahead of print.

Authors

Su-Jeong Kim¹, Brendan Miller¹, Nicolas G Hartel², Ricardo Ramirez 2nd¹, Regina Gonzalez Braniff¹, Naphada Leelaprachakul^{1

3}, Amy Huang¹, Yuzhu Wang¹, Thalida Em Arpawong¹, Eileen M Crimmins¹, Penglong Wang⁴, Xianbang Sun⁵, Chunyu Liu^{4

5

6}, Daniel Levy^{5

6}, Kelvin Yen¹, Giselle M Petzinger⁷, Nicholas A Graham^{1

2

8}, Michael W Jakowec^{7

9}, Pinchas Cohen¹⁰

Affiliations

¹ The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
² Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA.
³ Environmental Toxicology Program, Chulabhorn Graduate Institute, Bangkok, 10210, Thailand.
⁴ The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁶ Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
⁷ Department of Neurology, University of Southern California, Los Angeles, CA, USA.
⁸ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
⁹ Department of Biokinesiology and Physical Therapy, The George and MaryLou Boone Center for Parkinson's Disease Research, University of Southern California, Los Angeles, CA, USA.
¹⁰ The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA. hassy@usc.edu.

PMID: 38167865
DOI: 10.1038/s41380-023-02344-0

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.

Grants and funding

U01 AG009740/AG/NIA NIH HHS/United States