TY - JOUR

T1 - The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function

AU - Scheele, Camilla

AU - Petrovic, Natasa

AU - Faghihi, Mohammad A

AU - Lassmann, Timo

AU - Fredriksson, Katarina

AU - Rooyackers, Olav

AU - Wahlestedt, Claes

AU - Good, Liam

AU - Timmons, James A

PY - 2007/3/15

Y1 - 2007/3/15

N2 - 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.CONCLUSION: 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.

AB - 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.CONCLUSION: 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.

KW - Cell Line

KW - Gene Expression Regulation

KW - Humans

KW - Mitochondria

KW - Muscle, Skeletal

KW - Neurons

KW - Parkinson Disease

KW - Protein Isoforms

KW - Protein Kinases

KW - RNA, Antisense

KW - RNA, Double-Stranded

KW - RNA, Messenger

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1186/1471-2164-8-74

DO - 10.1186/1471-2164-8-74

M3 - Journal article

C2 - 17362513

VL - 8

SP - 74

JO - BMC Genomics

JF - BMC Genomics

SN - 1471-2164

ER -