Lindquist and collaborators show that overexpression of orthologs of the familial PD gene PARK9 in yeast and worm, and overexpression of human PARK9 in rat primary midbrain cultures suppresses α-synuclein (SNCA) toxicity in theses models. The genetic interaction between the two PD genes SNCA (PARK1) and ATP13A2 (PARK9) is exciting. This provocative observation suggests for the first time that these two previously unconnected PD genes may be involved in one single disease pathway.

This raises a number of questions: What precisely is this pathway and what exactly are the roles α-synuclein and ATP13A2 play in it? Is it ER-to-Golgi transport as the authors hint at, or could it be a lysosomal or other process? Unfortunately, little is known about the biological role of ATP13A2 other than its classification as a P-class ion pump and that it seems to localize to lysosomal membranes in COS7 cells. It will be important to clarify the subcellular localization and the biochemistry of this interaction, and substantiate the relevance of this link between SNCA and ATP13A2 for the human...  Read more

Lindquist and collaborators show that overexpression of orthologs of the familial PD gene PARK9 in yeast and worm, and overexpression of human PARK9 in rat primary midbrain cultures suppresses α-synuclein (SNCA) toxicity in theses models. The genetic interaction between the two PD genes SNCA (PARK1) and ATP13A2 (PARK9) is exciting. This provocative observation suggests for the first time that these two previously unconnected PD genes may be involved in one single disease pathway.

This raises a number of questions: What precisely is this pathway and what exactly are the roles α-synuclein and ATP13A2 play in it? Is it ER-to-Golgi transport as the authors hint at, or could it be a lysosomal or other process? Unfortunately, little is known about the biological role of ATP13A2 other than its classification as a P-class ion pump and that it seems to localize to lysosomal membranes in COS7 cells. It will be important to clarify the subcellular localization and the biochemistry of this interaction, and substantiate the relevance of this link between SNCA and ATP13A2 for the human disease, in human dopamine cells, and in the substantia nigra of patients with PD.

Exposure to manganese-containing fumes may make welders more prone to develop PD. In a second part of the study, Gitler et al. speculate about an additional role for PARK9 in this process. They indicate that yeast ATP13A2 modulates sensitivity of yeast cells to manganese exposure. This is an interesting hypothesis—but a lot more research is needed to clinch this.

View all comments by Clemens R. Scherzer

Could PARK9 and manganese toxicity have a role in ALS?

View all comments by robert ventullo

In this work, Susan Lindquist and colleagues from the Whitehead Institute reported a functional interaction between α-synuclein and the yeast ortholog of the Parkinson gene ATP13A2. Moreover, they showed that a knockdown of the corresponding ortholog in C. elegans enhanced α-synuclein misfolding. Finally, they demonstrated that the yeast ortholog could protect cells from manganese toxicity. This elegant work has, for the first time, demonstrated a functional link between two different Parkinson genes in combination with a recognized environmental factor—it contributes to an increased understanding of the complex mechanisms behind Parkinson disease.

View all comments by Martin Ingelsson

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