title: The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function.
abstract: BACKGROUND
  Mutations in the PTEN induced putative kinase 1 (PINK1) are implicated in early-onset Parkinson's disease. PINK1 is expressed abundantly in mitochondria rich tissues, such as skeletal muscle, where it plays a critical role determining mitochondrial structural integrity in Drosophila.
  
  
  RESULTS
  Herein we characterize a novel splice variant of PINK1 (svPINK1) that is homologous to the C-terminus regulatory domain of the protein kinase. Naturally occurring non-coding antisense provides sophisticated mechanisms for diversifying genomes and we describe a human specific non-coding antisense expressed at the PINK1 locus (naPINK1). We further demonstrate that PINK1 varies in vivo when human skeletal muscle mitochondrial content is enhanced, supporting the idea that PINK1 has a physiological role in mitochondrion. The observation of concordant regulation of svPINK1 and naPINK1 during in vivo mitochondrial biogenesis was confirmed using RNAi, where selective targeting of naPINK1 results in loss of the PINK1 splice variant in neuronal cell lines.
  
  
  CONCLUSIONS
  Our data presents the first direct observation that a mammalian non-coding antisense molecule can positively influence the abundance of a cis-transcribed mRNA under physiological abundance conditions. While our analysis implies a possible human specific and dsRNA-mediated mechanism for stabilizing the expression of svPINK1, it also points to a broader genomic strategy for regulating a human disease locus and increases the complexity through which alterations in the regulation of the PINK1 locus could occur.
authors.affiliation: Department of Cellular and Molecular Biology, Program for Genomics and Bioinformatics, Karolinska Institutet, Stockholm, Sweden. camilla.scheele@gmail.com <camilla.scheele@gmail.com>
authors.forename: Camilla
authors.initials: C
authors.lastname: Scheele
authors.forename: Natasa
authors.initials: N
authors.lastname: Petrovic
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Faghihi
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.forename: Katarina
authors.initials: K
authors.lastname: Fredriksson
authors.forename: Olav
authors.initials: O
authors.lastname: Rooyackers
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Liam
authors.initials: L
authors.lastname: Good
authors.forename: James A
authors.initials: JA
authors.lastname: Timmons
mesh_terms: D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D018482:Muscle, Skeletal; D009474:Neurons; D010300:Parkinson Disease / Q000235:genetics; D020033:Protein Isoforms; D011494:Protein Kinases / Q000235:genetics*; D016372:RNA, Antisense / Q000502:physiology*; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D000099202:PTEN-Induced Putative Kinase
chemical_list: D020033:Protein Isoforms; D011494:Protein Kinases; D016372:RNA, Antisense; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D000099202:PTEN-Induced Putative Kinase