Gitler et al. (see ARF related news story) previously demonstrated that ATP13A2/PARK9 functionally modified α-synuclein toxicity in yeast, and that its overexpression protected dopamine neurons in C. elegans from age-dependent α-synuclein degeneration. This excellent new study from Dehay and colleagues provides strong support for the hypothesis that ATP13A2/PARK9 activity is important for efficient lysosomal function and protein degradation. In the context of the growing literature on the shared cellular dysfunction underlying Gaucher's disease and Parkinson's disease (Mazzulli et al., 2011), these results extend the prospect that therapeutic interventions directed at enhancement of lysosomal-autophagy pathways represent an important target for PD research. The identification of genetic and protein modifiers of ATP13A2 activity may serve to elucidate additional mechanistic insights that can expand the potential for such therapies.

View all comments by Guy Caldwell

The lysosomal acidification defect linked to cytotoxicity of mutations in the P-type ATPase ATP13A2/PARK9 in Parkinson’s disease (PD) prompts comparison to the similar mechanism operating in AD due to mutations of presenilin 1. Dehay and colleagues used nearly the same extensive battery of methods as Lee et al. (2010) to evaluate autophagy and lysosomal function in fibroblasts from PD patients and other model cell systems. While the two studies implicate different lysosomal constituents in these two diseases, they reveal pathogenic mechanisms involving defects in lysosome function that are remarkably similar and mutually validating. In both diseases, a lysosomal component needed for acidification is prematurely degraded in the endoplasmic reticulum and fails to reach the lysosome in amounts required for full function. In early-onset AD caused by mutations of PS1, the V01a subunit of the proton pump vATPase is improperly chaperoned by the mutant PS1 and is degraded during its exit from the ER, similarly to the fate of mutant ATPase ATP13A2 in PD. Both molecules are large...  Read more

The lysosomal acidification defect linked to cytotoxicity of mutations in the P-type ATPase ATP13A2/PARK9 in Parkinson’s disease (PD) prompts comparison to the similar mechanism operating in AD due to mutations of presenilin 1. Dehay and colleagues used nearly the same extensive battery of methods as Lee et al. (2010) to evaluate autophagy and lysosomal function in fibroblasts from PD patients and other model cell systems. While the two studies implicate different lysosomal constituents in these two diseases, they reveal pathogenic mechanisms involving defects in lysosome function that are remarkably similar and mutually validating. In both diseases, a lysosomal component needed for acidification is prematurely degraded in the endoplasmic reticulum and fails to reach the lysosome in amounts required for full function. In early-onset AD caused by mutations of PS1, the V01a subunit of the proton pump vATPase is improperly chaperoned by the mutant PS1 and is degraded during its exit from the ER, similarly to the fate of mutant ATPase ATP13A2 in PD. Both molecules are large multi-pass membrane ATPases involved in H+ ion transport, although the role of ATPase ATP13A2 in lysosomal acidification is an exciting new finding.

The Dehay study raises an intriguing set of additional questions as to whether the lysosomes in specific neuron subtypes—dopaminergic neurons, in this case—are differentially regulated, why this might be, and how it might contribute to differential neuronal vulnerability. These findings reinforce the emerging concept of the lysosome as a vital regulator of diverse cell functions and as a highly vulnerable target in a growing number of neurodegenerative disorders affecting endocytosis and autophagy—processes that are especially crucial to neuron survival.

References:
Dehay B, Ramirez A, Martinez-Vicente M, Perier C, Canron MH, Doudnikoff E, Vital A, Vila M, Klein C, Bezard E. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc Natl Acad Sci U S A. 2012 109(24):9611-6. Abstract

Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010 Jun 25;141(7):1146-58. Abstract

View all comments by Ralph Nixon