AF6 protects against dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson's disease
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1
National Neuroscience Institute, Neurodegeneration Research Laboratory, Singapore
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2
National University of Singapore, Department of Physiology, Singapore
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3
Duke-NUS Medical School, Neuroscience and Behavioural Disorders, Singapore
Afadin 6 (AF6) is an F-actin binding multidomain-containing scaffolding protein that is better known for its function in cell-cell adhesion. However, besides its well documented role of AF6, we have recently found that AF6 is a novel Parkin-interacting protein that augments Parkin-mediated mitophagy and its level is significantly reduced in the brain of patients with Parkinson’s disease (PD) (Haskin et al., 2013). Notably, mutations in Parkin are associated with aberrant mitochondrial homeostasis and are causative of recessively inherited forms of PD. Given the role of AF6 in mitochondrial quality control, we hypothesized that AF6 overexpression may be beneficial to PD. Using Drosophila melanogaster as a model system, we demonstrate that transgenic overexpression of human AF6 in parkin null flies rescues their mitochondrial pathology and associated locomotion deficit, which results in their improved survival over time. Similarly, AF6 overexpression also ameliorates the pathological phenotypes induced by Leucine Rich Repeat Kinase 2 (LRRK2) G2019S mutant, a mutation that is associated with dominantly-inherited PD cases in humans. These include the restoration of dopamine level that is otherwise deficient in the brains of LRRK G2019S mutant flies. Conversely, when endogenous AF6 expression is silenced, it aggravates the diseased phenotypes of LRRK2 flies. Taken together, our results demonstrate that AF6 protects against dopaminergic dysfunction and mitochondrial abnormalities in multiple Drosophila genetic models of PD, and suggest the therapeutic value of AF6-related pathways in mitigating PD pathogenesis.
Acknowledgements
This work was supported by a grant from the National Medical Research Council of Singapore (NMRC-CBRG) to LKL.
Keywords:
Dopamine,
Drosophila,
Parkinson’s disease,
in vivo,
afadin 6
Conference:
14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016.
Presentation Type:
Poster Presentation Session
Topic:
14th Meeting of the Asian-Pacific Society for Neurochemistry
Citation:
Basil
AH,
Sim
JP,
Lin
S and
Lim
K
(2016). AF6 protects against dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson's disease.
Conference Abstract:
14th Meeting of the Asian-Pacific Society for Neurochemistry.
doi: 10.3389/conf.fncel.2016.36.00200
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Received:
04 Aug 2016;
Published Online:
11 Aug 2016.
*
Correspondence:
Ms. Adeline H Basil, National Neuroscience Institute, Neurodegeneration Research Laboratory, Singapore, Singapore, adelinehbasil@gmail.com