RRC ID 30478
著者 Imai Y, Kanao T, Sawada T, Kobayashi Y, Moriwaki Y, Ishida Y, Takeda K, Ichijo H, Lu B, Takahashi R.
タイトル The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila.
ジャーナル PLoS Genet
Abstract PTEN-induced kinase 1 (PINK1), which is required for mitochondrial homeostasis, is a gene product responsible for early-onset Parkinson's disease (PD). Another early onset PD gene product, Parkin, has been suggested to function downstream of the PINK1 signalling pathway based on genetic studies in Drosophila. PINK1 is a serine/threonine kinase with a predicted mitochondrial target sequence and a probable transmembrane domain at the N-terminus, while Parkin is a RING-finger protein with ubiquitin-ligase (E3) activity. However, how PINK1 and Parkin regulate mitochondrial activity is largely unknown. To explore the molecular mechanism underlying the interaction between PINK1 and Parkin, we biochemically purified PINK1-binding proteins from human cultured cells and screened the genes encoding these binding proteins using Drosophila PINK1 (dPINK1) models to isolate a molecule(s) involved in the PINK1 pathology. Here we report that a PINK1-binding mitochondrial protein, PGAM5, modulates the PINK1 pathway. Loss of Drosophila PGAM5 (dPGAM5) can suppress the muscle degeneration, motor defects, and shorter lifespan that result from dPINK1 inactivation and that can be attributed to mitochondrial degeneration. However, dPGAM5 inactivation fails to modulate the phenotypes of parkin mutant flies. Conversely, ectopic expression of dPGAM5 exacerbated the dPINK1 and Drosophila parkin (dParkin) phenotypes. These results suggest that PGAM5 negatively regulates the PINK1 pathway related to maintenance of the mitochondria and, furthermore, that PGAM5 acts between PINK1 and Parkin, or functions independently of Parkin downstream of PINK1.
巻・号 6(12)
ページ e1001229
公開日 2010-12-2
DOI 10.1371/journal.pgen.1001229
PMID 21151955
PMC PMC2996328
MeSH Animals Disease Models, Animal Down-Regulation* Drosophila / enzymology* Drosophila / genetics Drosophila Proteins / genetics Drosophila Proteins / metabolism* Gene Silencing* HEK293 Cells Humans Mitochondria / enzymology* Mitochondria / genetics Parkinson Disease / genetics Parkinson Disease / metabolism* Phosphoglycerate Kinase / genetics Phosphoglycerate Kinase / metabolism* Protein Binding Protein Kinases / genetics Protein Kinases / metabolism Protein Serine-Threonine Kinases / genetics* Protein Serine-Threonine Kinases / metabolism Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism
IF 5.175
引用数 53
WOS 分野 GENETICS & HEREDITY
リソース情報
ショウジョウバエ DGRC#109842 DGRC#109843 DGRC#118735 DGRC#118736 DGRC#118737 DGRC#118738