Evaluation of ATP13A2 as a Molecular Target for Ameliorating Alpha-Synuclein-Induced Neurodegeneration in Pre-clinical Models of PD
Target Validation, 2011
Mutations in the alpha-synuclein gene cause autosomal dominant Parkinsonís disease. While mutant forms of alpha-synuclein are toxic when introduced into neurons and pre-clinical brains, reasons for this are unclear. Recessive mutations in the ATP13A2 gene cause familial parkinsonism, and expression of non-mutated ATP13A2 was recently shown to protect against alpha-synuclein-induced toxicity in yeast, worm and neuronal models. Accordingly, we will evaluate ATP13A2 as a novel molecular target for preventing alpha-synuclein-induced neurodegeneration.
We will explore the potential neuroprotective function of ATP13A2 in two models of alpha-synuclein-induced neuronal toxicity. The effects of ATP13A2 on alpha-synuclein aggregation, striatal dopamine deficits and behavioral motor impairment induced by alpha-synuclein expression will also be assessed. Accordingly, we will determine whether modulation of ATP13A2 expression (and thus activity) constitutes a promising new molecular target for ameliorating alpha-synuclein-induced neuronal degeneration in vitro and in vivo.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:††
Our studies will evaluate the impact of a potential new target, ATP13A2, in a defined PD-relevant pre-clinical model based upon human alpha-synuclein. This study will clarify whether ATP13A2 plays a role in alpha-synuclein-induced neuronal degeneration, and may identify ATP13A2 or an ATP13A2-related pathway as a new drug target for preventing alpha-synuclein-induced degeneration. It is anticipated that our findings will be relevant for understanding the molecular mechanism(s) underlying both familial and sporadic PD.
This project will determine whether ATP13A2 constitutes a new molecular target for inferring with alpha-synuclein-induced neuronal damage and degeneration in cultured neurons and pre-clinical models of PD. Our studies will help to guide the development of future therapies based upon modulating neuronal toxicity induced by pathological forms of alpha-synuclein.
INTERIM PROGRESS REPORT
The main goal of our project is to evaluate ATP13A2 as a novel neuroprotective target for preventing neuronal damage induced by alpha-synuclein. Our studies so far have focused on assessing the impact of modulating the expression of ATP13A2 and alpha-synuclein on neuronal integrity and cell death in cultured neurons. We have also developed a number of reagents for modulating the expression of these two proteins in cultured cells and whole animals. Efforts to explore the functional interaction of ATP13A2 and alpha-synuclein in cultured neurons are ongoing. We hope to determine whether ATP13A2 can provide neuroprotection against neurotoxicity related to the expression of alpha-synuclein.
Presentations & Publications
Ramonet D, Podhajska A, Stafa K, Sonnay S, Trancikova A, Tsika E, Pletnikova O, Troncoso JC, Glauser L, Moore DJ. PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum. Mol. Genet. 2012, Jan 3 Epub.
Podhajska A, Musso A, Trancikova A, Glauser L, Sonnay S, Moore DJ. Common pathogenic effects of missense mutations in the P-type ATPase ATP13A2 (PARK9) associated with early-onset parkinsonism. PLoS One 2012, under revision.
Associate Professor, Center for Neurodegenerative Science and Head, Laboratory of Molecular Neurodegeneration at Van Andel Research Institute
Location: Grand Rapids, Michigan, United States