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.
Keywords: Autophagy; Caenorhabditis elegans; Osmotic stress; Parkinson's disease; ROS; α-Synuclein.
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