Although the etiology of Parkinson's disease (PD) is multifactorial, it has been linked to abnormal accumulation of α-synuclein (α-syn) in dopaminergic neurons, which could lead to dysfunctions on intracellular organelles, with potential neurodegeneration. Patients with familial early-onset PD frequently present mutation in the α-syn gene (SNCA), which encodes mutant α-syn forms, such as A30P and A53T, which potentially regulate Ca²⁺ unbalance. Here we investigated the effects of overexpression of wild-type α-syn (WT) and the mutant forms A30P and A53T, on modulation of lysosomal Ca²⁺ stores and further autophagy activation. We found that in α-syn-overexpressing cells, there was a decrease in Ca²⁺ released from endoplasmic reticulum (ER) which is related to the increase in lysosomal Ca²⁺ release, coupled to lysosomal pH alkalization. Interestingly, α-syn-overexpressing cells showed lower LAMP1 levels, and a disruption of lysosomal morphology and distribution, affecting autophagy. Interestingly, all these effects were more evident with A53T mutant isoform when compared to A30P and WT α-syn types, indicating that the pathogenic phenotype for PD is potentially related to impairment of α-syn degradation. Taken together, these events directly impact PD-related dysfunctions, being considered possible molecular targets for neuroprotection.

尽管帕金森病 (PD) 的病因是多因素的，但它与多巴胺能神经元中 α-突触核蛋白 (α-syn) 的异常积累有关，这可能导致细胞内细胞器功能障碍，并具有潜在的神经变性。家族性早发性 PD 患者经常出现 α-syn 基因 ( SNCA ) 突变，该基因编码突变的 α-syn 形式，例如 A30P 和 A53T，它们可能调节 Ca ²⁺失衡。在这里，我们研究了野生型 α-syn (WT) 和突变形式 A30P 和 A53T 过表达对溶酶体 Ca ²⁺储存的调节和进一步自噬激活的影响。我们发现在 α-syn 过表达的细胞中，Ca ^2+减少由内质网 (ER) 释放，这与溶酶体 Ca ²⁺释放的增加有关，与溶酶体 pH 碱化有关。有趣的是，α-syn 过表达细胞显示出较低的 LAMP1 水平，以及溶酶体形态和分布的破坏，从而影响自噬。有趣的是，与 A30P 和 WT α-syn 类型相比，A53T 突变体亚型的所有这些影响更明显，表明 PD 的致病表型可能与 α-syn 降解受损有关。总之，这些事件直接影响 PD 相关的功能障碍，被认为是神经保护的可能分子靶点。