title: AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson's disease.
abstract: Parkin E3 ubiquitin-ligase activity and its role in mitochondria homeostasis are thought to play a role in Parkinson's disease (PD). We now report that AF-6 is a novel parkin interacting protein that modulates parkin ubiquitin-ligase activity and mitochondrial roles. Parkin interacts with the AF-6 PDZ region through its C-terminus. This leads to ubiquitination of cytosolic AF-6 and its degradation by the proteasome. On the other hand, endogenous AF-6 robustly increases parkin translocation and ubiquitin-ligase activity at the mitochondria. Mitochondrial AF-6 is not a parkin substrate, but rather co-localizes with parkin and enhances mitochondria degradation through PINK1/parkin-mediated mitophagy. On the other hand, several parkin and PINK1 juvenile disease-mutants are insensitive to AF-6 effects. AF-6 is present in Lewy bodies and its soluble levels are strikingly decreased in the caudate/putamen and substantia nigra of sporadic PD patients, suggesting that decreased AF-6 levels may contribute to the accumulation of dysfunctional mitochondria in the disease. The identification of AF-6 as a positive modulator of parkin translocation to the mitochondria sheds light on the mechanisms involved in PD and underscores AF-6 as a novel target for future therapeutics.
authors: Department of Pharmacology, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Bat-Galim, Haifa, Israel.
authors: Joseph
authors: J
authors: Haskin
authors: Raymonde
authors: R
authors: Szargel
authors: Vered
authors: V
authors: Shani
authors: Lucy N
authors: LN
authors: Mekies
authors: Ruth
authors: R
authors: Rott
authors: Grace G Y
authors: GG
authors: Lim
authors: Kah-Leong
authors: KL
authors: Lim
authors: Rina
authors: R
authors: Bandopadhyay
authors: Herman
authors: H
authors: Wolosker
authors: Simone
authors: S
authors: Engelender
mesh_terms: D002421:Caudate Nucleus / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D016547:Kinesins; D009218:Myosins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C095516:AFDN protein, human; C111567:parkin protein
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