title: Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology.
abstract: α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3' untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3' untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3' untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.
authors.affiliation: Department of Pathology, Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403, 630 West 168th Street, New York, New York 10032, USA.
authors.forename: Herve
authors.initials: H
authors.lastname: Rhinn
authors.forename: Liang
authors.initials: L
authors.lastname: Qiang
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: David
authors.initials: D
authors.lastname: Rhee
authors.forename: Ari
authors.initials: A
authors.lastname: Zolin
authors.forename: William
authors.initials: W
authors.lastname: Vanti
authors.forename: Asa
authors.initials: A
authors.lastname: Abeliovich
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D051844:alpha-Synuclein; D004298:Dopamine