Abstract：
Endosomal acid base balance functions as a master orchestrator within the cell, engaging with many cellular pathways to maintain homeostasis. Mutations in the endosomal pH regulator Na+/H+ exchanger NHE6 may disrupt this delicate balancing act and cause monogenic Parkinsonism. Here, gene expression studies in post-mortem substantia nigra of Parkinson\'s disease (PD) patients and normal controls were performed to investigate whether NHE6 represents a pathophysiological link between monogenic and sporadic PD. The substantia nigra in PD displayed down-regulation of NHE6, coincident with a loss of expression of several SNARE signalling pathway members, suggesting impaired membrane fusion and vesicle-recycling. Increased abundance of related NHE9 was also identified in the parkinsonian nigra that could reflect compensatory changes or be a consequence of neuronal dysfunction. The current model suggests the possibility that neurons expressing low levels of NHE6 are more susceptible to injury in PD, potentially directly contributing to the loss of nigral dopaminergic neurons and the genesis of the disease. These results have important implications for disease-modifying therapies as they suggest that endosomal pH correctors, including epigenetic modifiers that regulate NHE6 expression, may be beneficial for PD. Thus, aberrant endosomal acidification in the nigrostriatal pathway is a possible unifying pathomechanism in both monogenic and sporadic PD, with implications for understanding and treating this disorder. Replication of these observations in the post-mortem brains of Alzheimer\'s disease and frontotemporal dementia patients supports a model of conserved mechanisms underlying injury and death of neurons.
摘要：
内体酸碱平衡作为细胞内的主协调器，参与许多细胞通路以维持体内平衡。内体pH调节剂Na/H交换剂NHE6的突变可能会破坏这种微妙的平衡行为并引起单基因帕金森病。这里,在帕金森病（PD）患者和正常对照的死后黑质中进行了基因表达研究，以调查NHE6是否代表单基因和散发性PD之间的病理生理联系。PD中的黑质显示NHE6的下调，同时几个SNARE信号通路成员的表达丧失，提示膜融合和囊泡再循环受损。在帕金森病黑质中也发现了相关NHE9的丰度增加，这可能反映了代偿性变化或神经元功能障碍的结果。目前的模型表明，表达低水平NHE6的神经元更容易受到PD损伤的可能性，可能直接导致黑质多巴胺能神经元的丧失和疾病的发生。这些结果对疾病改善疗法具有重要意义，因为它们表明内体pH值校正剂，包括调节NHE6表达的表观遗传修饰剂，可能对PD有益。因此，黑质纹状体途径中的异常内体酸化是单基因和散发性PD中可能的统一病理机制，对理解和治疗这种疾病有意义。这些观察结果在阿尔茨海默氏病和额颞叶痴呆患者的死后大脑中的复制支持了神经元损伤和死亡的保守机制模型。
