Novel therapeutic approaches for Parkinson's disease by targeting brain cholesterol homeostasis.

Abstract

Human brain is composed of 25% of the cholesterol & any dysfunction in brain cholesterol homeostasis contributes to neurodegenerative disorders such as Parkinson, Alzheimer's, Huntington's disease, etc. A growing literature indicates that alteration in neurotransmission & brain cholesterol metabolism takes place in the early stage of the disease. The current paper summarizes the role of cholesterol & its homeostasis in the pathophysiology of Parkinson's disease. Literature findings suggest the possible role of lipids such as oxysterols, lipoproteins, etc. in Parkinson's disease pathophysiology. Cholesterol performs a diverse role in the brain but any deviation in its levels leads to neurodegeneration. Dysregulation of lipid caused by oxidative stress & inflammation leads to α-synuclein trafficking which contributes to Parkinson's disease progression. Also, α-synuclein by binding to membrane lipid forms lipid-protein complex & results in its aggregation. Different targets such as Phospholipase A2, Stearoyl-CoA desaturase enzyme, proprotein convertase subtilisin/kexin type 9, etc. have been identified as a potential novel approach for Parkinson's disease treatment. In the current review, we have discussed the possible molecular role of cholesterol homeostasis in Parkinson's disease progression. We also identified potential therapeutic targets that need to be evaluated clinically for the development of Parkinson's treatment.