The new paper from Zhenyu Yue is very interesting, and certainly further implicates autophagy as a step involved in Parkinson's pathogenesis. This seems to provide support for other work from Richard Youle's (Narendra et al., 2010) and Charleen Chu's (Dagda et al., 2009) labs suggesting that a deficit in mitochondrial turnover by macroautophagy might occur with the parkin and PINK mutations that can cause some cases of PD. So, a mutation that directly affects macroautophagy may model a downstream step in PD. One possibility is that mutant α-synuclein first disturbs another form of autophagy, known as chaperone-mediated autophagy, and this leads to downstream consequences for macroautophagy. Thus, the similar (although not identical) ATG7 mutant mice, which both of our labs have developed, may mostly be modeling later stages in the disease.

View all comments by David Sulzer

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