Rhomboid-7 and HtrA2/Omi act in a common pathway with the Parkinson's disease factors Pink1 and Parkin.
Parkinson's disease (PD) is a common neurodegenerative disorder caused by loss of midbrain dopaminergic neurons, the pathogenetic mechanisms of which remain unclear. Mitochondrial dysfunction, which has long been implicated in sporadic PD, has recently been highlighted as a key pathological cause, particularly with the identification of mutations in the PTEN-induced putative kinase (pink1), parkin and htrA2 (also known as omi) genes that are linked to PD. Studies in Drosophila melanogaster have shown that pink1 and parkin act in a common genetic pathway that maintains mitochondrial integrity, but other upstream or downstream components of this pathway are currently unknown. Using ectopic expression in the Drosophila eye as an assay, we have investigated the involvement of the mitochondrial protease encoded by omi in the Pink1/Parkin pathway and found that it acts genetically downstream of pink1 but functions independently of Parkin. Using the same approach, we also found that Rhomboid-7, a mitochondrial protease not previously implicated in PD, acts as an upstream component of this pathway, and showed that it is required to cleave the precursor forms of both Pink1 and Omi. These data further elucidate the composition of the Pink1 pathway and suggest that regulated intramembrane proteolysis is involved in its regulation.
Whitworth
Alexander J
AJ
MRC Centre for Developmental and Biomedical Genetics, Department of Biomedical Sciences, University of Sheffield, Sheffield, S10 2TN, UK. a.whitworth@sheffield.ac.uk
Lee
Jeffrey R
JR
Ho
Venus M-W
VM
Flick
Robert
R
Chowdhury
Ruhena
R
McQuibban
G Angus
GA
D000818:Animals; D015153:Blotting, Western; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004331:Drosophila melanogaster; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006868:Hydrolysis; D007150:Immunohistochemistry; D008855:Microscopy, Electron, Scanning; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase
D029721:Drosophila Proteins; D000074923:High-Temperature Requirement A Serine Peptidase 2; D024101:Mitochondrial Proteins; D017346:Protein Serine-Threonine Kinases; D012697:Serine Endopeptidases; D044767:Ubiquitin-Protein Ligases; C513147:rho-7 protein, Drosophila; C534484:PINK1 protein, Drosophila; D000099202:PTEN-Induced Putative Kinase; C530280:HtrA2 protein, Drosophila; C487430:park protein, Drosophila