Parkinson''s disease (PD) is an age-dependent neurodegenerative disease characterized by the accumulation of alpha-synuclein (alpha-syn) and the selective loss of dopamine (DA) neurons; studies in C. elegans models of alpha-syn proteotoxcity indicate that reduced IGF-1/insulin-like signaling (IIS) suppresses alpha-syn toxicity and DA neurodegeneration; specifically daf-2 mutant worms that overexpress human alpha-syn retain more wild-type DA neurons when compared to alpha-syn worms alone; mutants of daf-16/FOXO, a well-characterized downstream component of the IIS pathway enhanced neurodegeneration, and an intermediate level of neuroprotection was seen in daf-2; daf-16 double mutants overexpressing alpha-syn-GFP in DA neurons; further, RNA interference of glucose-6-phosphate isomerase (gpi-1/GPI), the glycolytic enzyme, enhanced alpha-syn-induced DA neurotoxicity, while it''s overexpression in DA neurons was neuroprotective; further studies in Drosophila and mice confirm that GPI is neuroprotective; these studies indicate that IIS signaling modulates alpha-syn induced DA neurodegeneration, across species.
In glucose-fed wild-type animals, the exponential like decline was restored in the active state, indicating that insulin signaling may be involved in regulation of fractal scaling of C. elegans behavior.