title: Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for ERK-MAPK signaling.
abstract: Parkinson's disease (PD) is a currently incurable neurodegenerative disorder that affects the aging population. The loss of dopaminergic neurons in the substantia nigra is one of the pathological features of PD. The precise causes of PD remain unresolved but evidence supports both environmental and genetic contributions. Current efforts for the treatment of PD are directed toward the discovery of compounds that show promise in impeding age-dependent neurodegeneration in PD patients. Alpha-synuclein (α-Syn) is a human protein that is mutated in specific populations of patients with familial PD. Overexpression of α-Syn in animal models of PD replicates key symptoms of PD, including neurodegeneration. Here, we use the nematode Caenorhabditis elegans as a model system, whereby α-Syn toxicity causes dopaminergic neurodegeneration, to test the capacity of valproic acid (VA) to protect neurons. The results of our study showed that treatment of nematodes with moderate concentrations of VA significantly protects dopaminergic neurons against α-Syn toxicity. Consistent with previously established knowledge related to the mechanistic action of VA in the cell, we showed through genetic analysis that the neuroprotection conferred by VA is inhibited by cell-specific depletion of the C. elegans ortholog of the MAP extracellular signal-regulated kinase (ERK), MPK-1, in the dopaminergic neurons. These findings suggest that VA may exert its neuroprotective effect via ERK-MAPK, or alternately could act with MAPK signaling to additively provide dopaminergic neuroprotection.
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, United States.
authors.forename: Bwarenaba B
authors.initials: BB
authors.lastname: Kautu
authors.forename: Alejandro
authors.initials: A
authors.lastname: Carrasquilla
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Hicks
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology; D034622:RNA Interference; D014635:Valproic Acid / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D029742:Caenorhabditis elegans Proteins; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D014635:Valproic Acid; D019950:Mitogen-Activated Protein Kinase 1; C085697:mpk-1 protein, C elegans; D048370:MAP Kinase Kinase 2