Jishi Aya, Hu Di, Shang Yutong, Wang Rihua, Gunzler Steven A, Qi Xin
Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
Center for Mitochondrial Research and Therapeutics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.
Acta Neuropathol Commun. 2024 Dec 21;12(1):198. doi: 10.1186/s40478-024-01915-8.
Mitochondrial dysfunction and α-synuclein (αSyn) aggregation are key contributors to Parkinson's Disease (PD). While genetic and environmental risk factors, including mutations in mitochondrial-associated genes, are implicated in PD, the precise mechanisms linking mitochondrial defects to αSyn pathology remain incompletely understood, hindering the development of effective therapeutic interventions. Here, we identify the loss of branched chain ketoacid dehydrogenase kinase (BCKDK) as a mitochondrial risk factor that exacerbates αSyn pathology by disrupting Complex I function. Our findings reveal a consistent downregulation of BCKDK in dopaminergic (DA) neurons from A53T-αSyn mouse models, PD patient-derived induced pluripotent stem (iPS) cells, and postmortem brain tissues. BCKDK deficiency leads to mitochondrial dysfunction, including reduced membrane potential and increased reactive oxygen species (ROS) production upon administration of a stressor, which in turn promotes αSyn oligomerization. Mechanistically, BCKDK interacts with the NDUFS1 subunit of Complex I to stabilize its function. Loss of BCKDK disrupts this interaction, leading to Complex I destabilization and enhanced αSyn aggregation. Notably, restoring BCKDK expression in neuron-like cells rescues mitochondrial integrity and restores Complex I activity. Similarly, in patient-derived iPS cells differentiated to form dopaminergic neurons, NDUFS1 and phosphorylated aSyn levels are partially restored upon BCKDK expression. These findings establish a mechanistic link between BCKDK deficiency, mitochondrial dysfunction, and αSyn pathology in PD, positioning BCKDK as a potential therapeutic target to mitigate mitochondrial impairment and neurodegeneration in PD.
线粒体功能障碍和α-突触核蛋白（αSyn）聚集是帕金森病（PD）的关键促成因素。虽然包括线粒体相关基因突变在内的遗传和环境风险因素与PD有关，但将线粒体缺陷与αSyn病理联系起来的精确机制仍未完全了解，这阻碍了有效治疗干预措施的开发。在这里，我们确定支链酮酸脱氢酶激酶（BCKDK）的缺失是一种线粒体风险因素，它通过破坏复合体I的功能来加剧αSyn病理。我们的研究结果显示，在A53T-αSyn小鼠模型、PD患者来源的诱导多能干细胞（iPS）以及死后脑组织的多巴胺能（DA）神经元中，BCKDK持续下调。BCKDK缺乏会导致线粒体功能障碍，包括膜电位降低以及在施加应激源时活性氧（ROS）生成增加，进而促进αSyn寡聚化。从机制上讲，BCKDK与复合体I的亚基NDUFS1相互作用以稳定其功能。BCKDK的缺失破坏了这种相互作用，导致复合体I不稳定并增强αSyn聚集。值得注意的是，在类神经元细胞中恢复BCKDK表达可挽救线粒体完整性并恢复复合体I活性。同样，在分化形成多巴胺能神经元的患者来源的iPS细胞中，BCKDK表达后NDUFS1和磷酸化αSyn水平会部分恢复。这些发现建立了BCKDK缺乏、线粒体功能障碍与PD中αSyn病理之间的机制联系，将BCKDK定位为减轻PD中线粒体损伤和神经退行性变的潜在治疗靶点。
