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.
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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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