title: α-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson's disease occurs independent of ATP13A2 (PARK9).
abstract: Mutations in the ATP13A2 (PARK9) gene cause early-onset, autosomal recessive Parkinson's disease (PD) and Kufor-Rakeb syndrome. ATP13A2 mRNA is spliced into three distinct isoforms encoding a P5-type ATPase involved in regulating heavy metal transport across vesicular membranes. Here, we demonstrate that three ATP13A2 mRNA isoforms are expressed in the normal human brain and are modestly increased in the cingulate cortex of PD cases. ATP13A2 can mediate protection toward a number of stressors in mammalian cells and can protect against α-synuclein-induced toxicity in cellular and invertebrate models of PD. Using a primary cortical neuronal model combined with lentiviral-mediated gene transfer, we demonstrate that human ATP13A2 isoforms 1 and 2 display selective neuroprotective effects toward toxicity induced by manganese and hydrogen peroxide exposure through an ATPase-independent mechanism. The familial PD mutations, F182L and G504R, abolish the neuroprotective effects of ATP13A2 consistent with a loss-of-function mechanism. We further demonstrate that the AAV-mediated overexpression of human ATP13A2 is not sufficient to attenuate dopaminergic neurodegeneration, neuropathology, and striatal dopamine and motoric deficits induced by human α-synuclein expression in a rat model of PD. Intriguingly, the delivery of an ATPase-deficient form of ATP13A2 (D513N) to the substantia nigra is sufficient to induce dopaminergic neuronal degeneration and motor deficits in rats, potentially suggesting a dominant-negative mechanism of action. Collectively, our data demonstrate a distinct lack of ATP13A2-mediated protection against α-synuclein-induced neurotoxicity in the rat nigrostriatal dopaminergic pathway, and limited neuroprotective capacity overall, and raise doubts about the potential of ATP13A2 as a therapeutic target for PD.
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Daniel
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musso
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Elpida
authors.initials: E
authors.lastname: Tsika
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Aris
authors.initials: A
authors.lastname: Fiser
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Liliane
authors.initials: L
authors.lastname: Glauser
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Neurodegenerative Disease Laboratory, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: Darren.Moore@vai.org.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008297:Male; D008345:Manganese / Q000633:toxicity*; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014015:Tissue Banks; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C514983:ATP13A2 protein, human; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D008345:Manganese; D006861:Hydrogen Peroxide; D006180:Proton-Translocating ATPases
keywords: ATP13A2; Alpha-synuclein; Heavy metals; Kufor–Rakeb syndrome; PARK9; Parkinsonism