Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

Abstract

Protein stabilizers/chemical chaperones/osmolytes find significant industrial application in maintaining the native state of proteins and averting their misfolding or aggregation during repetitive freeze-thawing and various other stresses. Existing literature presents evidence towards possible therapeutic benefits of these protein stabilizers in evading or delaying disorders arising from protein misfolding and aggregation, usually termed as proteo-pathies. Parkinson's disease (PD) is one such disorder marked with alpha synuclein aggregation forming inclusions resulting in dopaminergic neurodegeneration and impaired motor function. We carried out this study in order to delineate the potential of protein stabilizers in attenuating manifestations associated with parkinsonism using a transgenic Caenorhabditis elegans model expressing human alpha synuclein. We studied protein stabilizers sorbitol, trehalose and xylitol and evaluated various endpoints associated with alpha synuclein aggregation. Lower concentrations of protein stabilizers were inefficient in exhibiting any effect, however a higher concentration (10 mM) did exhibit a significant effect on the studied phenotypes. Trehalose, at 10 mM concentration, showed reduction in alpha synuclein levels and reactive oxygen species, while showing significant increase in motility, dopamine levels and up-regulation of autophagic and chaperonic genes bec-1, lgg-1, epg-8, hsp-60 and hsp-4 in alpha synuclein expressing model, implicating its beneficial effects in parkinsonism. Our studies established the potential role of trehalose in alleviating manifestations associated with parkinsonism via its inherent activity and through induction of autophagic machinery in vivo. We conclude that these chemical chaperones have potential in being used as a supplementary therapeutic intervention addressing the important factor of protein aggregation in neurodegenerative Parkinson's disease. Further research on the subject will be required towards establishing their mechanism of action and suitability of such intervention, possibly along with existing therapies that address other important factors of the disease.