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.