Parkin co-regulated gene is involved in aggresome formation and autophagy in response to proteasomal impairment.
PArkin Co-Regulated Gene is a gene that shares a bidirectional promoter with the Parkinson's disease associated gene parkin. The encoded protein (PACRG) is found in Lewy bodies and glial cytoplasmic inclusions, the pathological hallmarks of parkinsonian disorders. To investigate the function and regulation of PACRG, cells were treated with the proteasomal inhibitor, MG-132. As previously reported with parkin, inhibition of the proteasome resulted in the formation of aggresomes that contained endogenous PACRG. Increased levels of exogenous PACRG resulted in an increase in aggresome formation, and conferred significant resistance to aggresome disruption and cell death mediated by microtubule depolymerisation. In contrast, shRNA mediated knockdown of PACRG significantly reduced aggresome numbers. Elevated levels of PACRG also resulted in increased autophagy, as demonstrated by biochemical and quantitative analysis of autophagic vesicles, whereas lowered levels of PACRG resulted in reduced autophagy. These results suggest a role for PACRG in aggresome formation and establish a further link between the UPS and autophagy.
Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Victoria, Australia. juliett@unimelb.edu.au
Juliet M
JM
Taylor
Kate M
KM
Brody
Paul J
PJ
Lockhart
D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016631:Lewy Bodies / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
D007976:Leupeptins; D008840:Microfilament Proteins; D018832:Molecular Chaperones; C471711:PACRG protein, human; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde