期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 48, 页码 16076-16085出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1945-14.2014
关键词
alpha-synuclein; C. elegans; dopamine; neuroprotection; Parkinson's; RNA
资金
- National Institutes of Health Office Research Infrastructure Programs [P40 OD010440]
- National Institutes of Health [R15 NS075684, R15 NS078728]
- Howard Hughes Medical Institute Undergraduate Science Program
- Parkinson's Support Group of Huntsville
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R15NS075684, R15NS078728] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [P40OD010440] Funding Source: NIH RePORTER
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 alpha-synuclein (alpha-syn) protein. RNA interference (RNAi) screening using Caenorhabditis elegans identified RTCB-1, an uncharacterized gene product, as one of several significant modifiers of alpha-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 alpha-syn. Moreover, neuronal-specific RNAi depletion of rtcb-1 enhanced alpha-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.
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