title: RTCB-1 mediates neuroprotection via XBP-1 mRNA splicing in the unfolded protein response pathway.
abstract: Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is characterized by the degeneration of dopamine (DA) neurons and age-dependent formation of protein inclusions that contain the α-synuclein (α-syn) protein. RNA interference (RNAi) screening using Caenorhabditis elegans identified RTCB-1, an uncharacterized gene product, as one of several significant modifiers of α-syn protein misfolding. RTCB-1 is the worm ortholog of the human HSPC117 protein, a component of RNA trafficking granules in mammalian neurons. Here we show that RTCB-1 protects C. elegans DA neurons from age-dependent degeneration induced by human α-syn. Moreover, neuronal-specific RNAi depletion of rtcb-1 enhanced α-syn-induced degeneration. Similar results were obtained when worms were exposed to the DA neurotoxin 6-hydroxydopamine. HSPC117 has been characterized recently as an essential subunit of the human tRNA splicing ligase complex. tRNA ligases have alternative functions in RNA repair and nonconventional mRNA splicing events. For example, in yeast, unconventional splicing of HAC1, a transcription factor that controls the unfolded protein response (UPR), is mediated by a tRNA ligase. In C. elegans, we demonstrate that RTCB-1 is necessary for xbp-1 (worm homolog of HAC1) mRNA splicing. Moreover, using a RNA ligase-dead mutant, we determine that the ligase activity of worm RTCB-1 is required for its neuroprotective role, which, in turn, is mediated through XBP-1 in the UPR pathway. Collectively, these studies highlight the mechanistic intersection of RNA processing and proteostasis in mediating neuroprotection.
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487, and.
authors.forename: Arpita
authors.initials: A
authors.lastname: Ray
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487, and.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487, and.
authors.forename: Courtney
authors.initials: C
authors.lastname: Rentas
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487, and Departments of Neurobiology and Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.affiliation: Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487, and Departments of Neurobiology and Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294 gcaldwel@ua.edu.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000517:prevention & control; D011506:Proteins / Q000502:physiology*; D012326:RNA Splicing / Q000502:physiology*; D056811:Unfolded Protein Response / Q000502:physiology*; D051844:alpha-Synuclein / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D011506:Proteins; C556193:RTCB protein, human; C548541:XBP-1 protein, C elegans; D051844:alpha-Synuclein
keywords: C. elegans; Parkinson's; RNA; alpha-synuclein; dopamine; neuroprotection