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AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson's disease.

Haskin, J; Szargel, R; Shani, V; Mekies, LN; Rott, R; Lim, GG; Lim, KL; ... Engelender, S; + view all (2013) AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson's disease. Hum Mol Genet , 22 (10) 2083 - 2096. 10.1093/hmg/ddt058. Green open access

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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.

Type: Article
Title: AF-6 is a positive modulator of the PINK1/parkin pathway and is deficient in Parkinson's disease.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddt058
Publisher version: http://dx.doi.org/10.1093/hmg/ddt058
Language: English
Additional information: # The Author 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommon- s.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. PMCID: PMC3803144
Keywords: Caudate Nucleus, HEK293 Cells, Humans, Kinesin, Mitochondria, Mutation, Myosins, Parkinson Disease, Protein Kinases, Protein Transport, Proteolysis, Substantia Nigra, Ubiquitin-Protein Ligases, Ubiquitination
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1385450
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