TY - JOUR
T1 - α-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson's disease occurs independent of ATP13A2 (PARK9)
AU - Daniel, Guillaume
AU - Musso, Alessandra
AU - Tsika, Elpida
AU - Fiser, Aris
AU - Glauser, Liliane
AU - Pletnikova, Olga
AU - Schneider, Bernard L.
AU - Moore, Darren J.
N1 - Funding Information:
This work was supported by funding from the Michael J. Fox Foundation for Parkinson's Research (D.J.M.), the Swiss National Science Foundation (Grant Nos. 310030_127478 and 31003A_144063 to D.J.M.), EPFL (D.J.M.), Van Andel Research Institute (D.J.M.), Johns Hopkins University Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 NS38377 ) and JHU Alzheimer's Disease Research Center ( NIA P50 AG05146 ).
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - ATP13A2
KW - Alpha-synuclein
KW - Heavy metals
KW - Kufor-Rakeb syndrome
KW - PARK9
KW - Parkinsonism
UR - http://www.scopus.com/inward/record.url?scp=84908541837&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84908541837&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2014.10.007
DO - 10.1016/j.nbd.2014.10.007
M3 - Article
C2 - 25461191
AN - SCOPUS:84908541837
SN - 0969-9961
VL - 73
SP - 229
EP - 243
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -