title: Nitrosative stress mediated misfolded protein aggregation mitigated by Na-D-β-hydroxybutyrate intervention.
abstract: Mitochondrial dysfunction, leading to elevated levels of reactive oxygen species, is associated with the pathogenesis of neurodegenerative disorders. Rotenone, a mitochondrial stressor induces caspase-9 and caspase-3 activation leading proteolytic cleavage of substrate nuclear poly(ADP-ribose) polymerase (PARP). PARP cleavage is directly related to apoptotic cell death. In this study, we have monitored the aggregation of green-fluorescent protein (GFP)-tagged synphilin-1, as a rotenone-induced Parkinsonia-onset biomarker. We report that the innate ketone body, Na-D-β-hydroxybutyrate (NaβHB) reduces markedly the incidence of synphilin-1 aggregation. Furthermore, our data reveal that the metabolic byproduct also prevents rotenone-induced caspase-activated apoptotic cell death in dopaminergic SH-SY5Y cells. Together, these results suggest that NaβHB is neuroprotective; it attenuates effects originating from mitochondrial insult and can serve as a scaffold for the design and development of sporadic neuropathies.
authors.affiliation: Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968, USA.
authors.forename: Parijat
authors.initials: P
authors.lastname: Kabiraj
authors.forename: Rituraj
authors.initials: R
authors.lastname: Pal
authors.forename: Armando
authors.initials: A
authors.lastname: Varela-Ramirez
authors.forename: Manuel
authors.initials: M
authors.lastname: Miranda
authors.forename: Mahesh
authors.initials: M
authors.lastname: Narayan
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000378:metabolism; D006801:Humans; D028361:Mitochondrial Diseases / Q000378:metabolism; D009336:Necrosis; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009566:Nitrates / Q000378:metabolism*; D015538:Nitrosation; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D012402:Rotenone / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009566:Nitrates; C118958:SNCAIP protein, human; D012402:Rotenone; D049452:Green Fluorescent Proteins; D020169:Caspases; D020155:3-Hydroxybutyric Acid