The accumulation of aggregate-prone proteins is a major representative of many neurological disorders, including Parkinson's disease (PD) wherein the cellular clearance mechanisms, such as the ubiquitin-proteasome and autophagy pathways are impaired. PD, known to be associated with multiple genetic and environmental factors, is characterized by the aggregation of α-synuclein protein and loss of dopaminergic neurons in midbrain. This disease is also associated with other cardiovascular ailments. Herein, we report our findings from studies on the effect of hyper and hypo-osmotic induced toxicity representing hyper and hypotensive condition as an extrinsic epigenetic factor towards modulation of Parkinsonism, using a genetic model Caenorhabditis elegans (C. elegans). Our studies showed that osmotic toxicity had an adverse effect on α-synuclein aggregation, autophagic puncta, lipid content and oxidative stress. Further, we figure that reduced autophagic activity may cause the inefficient clearance of α-synuclein aggregates in osmotic stress toxicity, thereby promoting α-synuclein deposition. Pharmacological induction of autophagy by spermidine proved to be a useful mechanism for protecting cells against the toxic effects of these proteins in such stress conditions. Our studies provide evidence that autophagy is required for the removal of aggregated proteins in these conditions. Studying specific autophagy pathways, we observe that the osmotic stress induced toxicity was largely associated with atg-7 and lgg-1 dependent autophagy pathway, brought together by involvement of mTOR pathway. This represents a unifying pathway to disease in hyper- and hypo-osmotic conditions within PD model of C. elegans.

易聚集蛋白的积累是许多神经系统疾病的主要代表，其中包括帕金森氏病（PD），其中细胞清除机制（如泛素-蛋白酶体和自噬途径）受损。PD，已知与多种遗传和环境因素有关，其特征在于α-突触核蛋白的聚集和中脑多巴胺能神经元的丢失。该疾病还与其他心血管疾病有关。在这里，我们报告使用遗传模型秀丽隐杆线虫（C. elegans）进行的高渗和低渗诱导的毒性作用的研究结果，这些毒性代表高渗和降压状况，是对帕金森氏症进行调制的外在表观遗传因子。我们的研究表明，渗透毒性对α-突触核蛋白的聚集，自噬点，脂质含量和氧化应激有不利影响。此外，我们认为自噬活性降低可能会导致渗透压毒性中α-突触核蛋白聚集体的清除效率低下，从而促进α-突触核蛋白沉积。在这种应激条件下，亚精胺的药理学诱导自噬被证明是保护细胞免受这些蛋白质毒性作用的有用机制。我们的研究提供了证据，表明在这些条件下自噬是去除聚集蛋白的必要条件。通过研究特定的自噬途径，我们观察到渗透胁迫诱导的毒性与atg-7和lgg-1密切相关依赖的自噬途径，通过mTOR途径的参与而汇集在一起​​。这代表线虫PD模型内高渗和低渗条件下疾病的统一途径。