Molecular Psychiatry ( IF 9.6 ) Pub Date : 2024-01-03 , DOI: 10.1038/s41380-023-02344-0
Su-Jeong Kim 1 , Brendan Miller 1 , Nicolas G Hartel 2 , Ricardo Ramirez 1 , Regina Gonzalez Braniff 1 , Naphada Leelaprachakul 1, 3 , Amy Huang 1 , Yuzhu Wang 1 , Thalida Em Arpawong 1 , Eileen M Crimmins 1 , Penglong Wang 4 , Xianbang Sun 5 , Chunyu Liu 4, 5, 6 , Daniel Levy 5, 6 , Kelvin Yen 1 , Giselle M Petzinger 7 , Nicholas A Graham 1, 2, 8 , Michael W Jakowec 7, 9 , Pinchas Cohen 1
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.
中文翻译:
SHLP2 的天然变体是帕金森病的保护因素
线粒体 DNA 单核苷酸多态性 (mtSNP) 与降低患帕金森病 (PD) 的风险有关,但其潜在机制仍然难以捉摸。在本研究中,我们研究了 PD 相关 mtSNP 的功能作用,该 mtSNP 影响线粒体衍生肽 (MDP) 小护脑素样肽 2 (SHLP2)。我们在编码 SHLP2 的小开放读码框中确定了 m.2158 T > C,这是一种与降低 PD 风险相关的 mtSNP。该 mtSNP 产生 SHLP2 的替代形式(赖氨酸 4 替换为精氨酸;K4R)。使用靶向质谱法,我们检测神经元细胞中 SHLP2 的特定胰蛋白酶片段,并证明其与线粒体复合物 1 的结合。值得注意的是,我们观察到与降低 PD 风险相关的 K4R 变体与 WT SHLP2 相比表现出更高的稳定性。此外,WT 和 K4R SHLP2 在体外实验中均表现出增强的针对线粒体功能障碍的保护作用,并在小鼠模型中针对 PD 诱导毒素(一种线粒体复合物 1 抑制剂)提供保护。这项研究揭示了 m.2158 T > C mtSNP 对 SHLP2 的功能影响,并深入了解该 mtSNP 降低 PD 风险的潜在机制。