title: A greatly extended PPARGC1A genomic locus encodes several new brain-specific isoforms and influences Huntington disease age of onset.
abstract: PGC-1α has been implicated in the pathogenesis of neurodegenerative disorders. Several single-nucleotide polymorphisms (SNPs) located in two separate haplotype blocks of PPARGC1A have shown associations with Huntington's disease (HD) and Parkinson's disease, but causative SNPs have not been identified. One SNP (rs7665116) was located in a highly conserved 233 bp region of intron 2. To determine whether rs7665116 is located in an alternative exon, we performed 5'-RLM-RACE from exon 3 and discovered multiple new transcripts that initiated from a common novel promoter located 587 kb upstream of exon 2, but did not contain the conserved region harboring rs7665116. Using real-time polymerase chain reaction, RNase protection assays and northern blotting, we show that the majority of these transcripts are brain specific and are at least equally or perhaps more abundant than the reference sequence PPARGC1A transcripts in whole brain. Two main transcripts containing independent methionine start codons encode full-length brain-specific PGC-1α proteins that differ only at their N-termini (NTs) from PGC-1α, encoded by the reference sequence. Additional truncated isoforms containing these NTs that are similar to NT-PGC-1α exist. Other transcripts may encode potential dominant negative forms, as they are predicted to lack the second LXXLL motif that serves as an interaction site for several nuclear receptors. Furthermore, we show that the new promoter is active in neuronal cell lines and describe haplotypes encompassing this region that are associated with HD age of onset. The discovery of such a large PPARGC1A genomic locus and multiple isoforms in brain warrants further functional studies and may provide new tissue-specific targets for treating neurodegenerative diseases.
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.
authors.forename: Selma M
authors.initials: SM
authors.lastname: Soyal
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Felder
authors.forename: Simon
authors.initials: S
authors.lastname: Auer
authors.forename: Penelope
authors.initials: P
authors.lastname: Hahne
authors.forename: Hannes
authors.initials: H
authors.lastname: Oberkofler
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.forename: Markus
authors.initials: M
authors.lastname: Paulmichl
authors.forename: G Bernhard
authors.initials: GB
authors.lastname: Landwehrmeyer
authors.forename: Patrick
authors.initials: P
authors.lastname: Weydt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
mesh_terms: D017668:Age of Onset; D001921:Brain / Q000378:metabolism*; D005091:Exons; D015894:Genome, Human; D023281:Genomics; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000453:epidemiology* / Q000235:genetics*; D007438:Introns; D008969:Molecular Sequence Data; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms; D014157:Transcription Factors