title: Trehalose does not improve neuronal survival on exposure to alpha-synuclein pre-formed fibrils.
abstract: Parkinson's disease is a debilitating neurodegenerative disorder that is pathologically characterized by intracellular inclusions comprised primarily of alpha-synuclein (αSyn) that can also be transmitted from neuron to neuron. Several lines of evidence suggest that these inclusions cause neurodegeneration. Thus exploring strategies to improve neuronal survival in neurons with αSyn aggregates is critical. Previously, exposure to αSyn pre-formed fibrils (PFFs) has been shown to induce aggregation of endogenous αSyn resulting in cell death that is exacerbated by either starvation or inhibition of mTOR by rapamycin, both of which are able to induce autophagy, an intracellular protein degradation pathway. Since mTOR inhibition may also inhibit protein synthesis and starvation itself can be detrimental to neuronal survival, we investigated the effects of autophagy induction on neurons with αSyn inclusions by a starvation and mTOR-independent autophagy induction mechanism. We exposed mouse primary cortical neurons to PFFs to induce inclusion formation in the presence and absence of the disaccharide trehalose, which has been proposed to induce autophagy and stimulate lysosomal biogenesis. As expected, we observed that on exposure to PFFs, there was increased abundance of pS129-αSyn aggregates and cell death. Trehalose alone increased LC3-II levels, consistent with increased autophagosome levels that remained elevated with PFF exposure. Interestingly, trehalose alone increased cell viability over a 14-d time course. Trehalose was also able to restore cell viability to control levels, but PFFs still exhibited toxic effects on the cells. These data provide essential information regarding effects of trehalose on αSyn accumulation and neuronal survival on exposure to PFF.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, USA; Center for Free Radical Biology, University of Alabama at Birmingham, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Redmann
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, USA; Center for Free Radical Biology, University of Alabama at Birmingham, USA.
authors.forename: Willayat Y
authors.initials: WY
authors.lastname: Wani
authors.affiliation: Center for Neurodegeneration, Experimental Therapeutics, University of Alabama at Birmingham, USA; Department of Neurology, University of Alabama at Birmingham, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Volpicelli-Daley
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, USA; Center for Free Radical Biology, University of Alabama at Birmingham, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, USA; Center for Free Radical Biology, University of Alabama at Birmingham, USA; Center for Neurodegeneration, Experimental Therapeutics, University of Alabama at Birmingham, USA; Department of Veterans Affairs, Birmingham VA Medical Center, USA. Electronic address: zhanja@uab.edu.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014199:Trehalose / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D014199:Trehalose; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Alpha-synuclein fibrils; Autophagy; LC3-II; P-alpha-synuclein trehalose; Parkinson's disease