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. PubMed.
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University of California, San Diego
In this study, Lee and colleagues describe a novel function of presenilin-1 (PS1), a protein previously found and best characterized as being involved in γ-secretase cleavage of amyloid precursor protein (APP) and Notch. The authors report that PS1 knockout cells exhibit a marked reduction in autolysosomal protein degradation in response to autophagy activation induced by serum starvation. On the subcellular level, these PS1 knockout cells present a phenotype that resembles histopathological changes in Alzheimer disease brains: the accumulation of numerous membrane-bound vesicles of the autolysosomal pathway (autophagosomes, early and late autolysosomes) that are filled with amorphous, undigested, electron-dense material.
Furthermore, the authors provide evidence for impaired maturation of cathepsin D, an important lysosomal protease, in the PS1 knockout cells. They show that this deficiency is due to reduced acidification of the lysosomal lumen. In a comprehensive attempt to identify the underlying mechanistic defects, Lee and colleagues discovered the involvement of PS1 in the maturation and localization of v-ATPase V0a1. This proton pump is important to establish a low intra-lysosomal pH. PS1 directly binds to the ATPase, modulates its glycosylation state, and in this way modifies the ATPase's maturation, degradation, and subcellular localization. The authors conclude that PS1 knockout causes decreased levels of mature v-ATPase V0a1, which in turn leads to impaired lysosomal acidification and decreased lysosomal proteolysis. They continue to support this hypothesis with data from PS1 hypomorphic mice and from AD patients' fibroblasts. In the hypomorphic mice PS1 levels are high enough to sustain Notch cleavage and prevent developmental defects, but appear insufficient to maintain normal lysosomal protein turnover. In the AD fibroblasts, certain PS1 mutations seem to strongly inhibit proteolysis, indicating that these mutations likely play a role in PS1-v-ATPase V0a1 interactions. Lee and colleagues thus propose a novel function of PS1 in lysosomal acidification, based on v-ATPase V0a1 maturation, which could be contributing to the observed accumulation of aberrant autophagosomes and lysosomes in AD patients’ brain tissue.
The recent report from Randy Nixon and colleagues is an interesting development in the story of familial Alzheimer disease (FAD) and its molecular roots. It is established that autophagy is deficient in the neurons of Alzheimer disease patients and that increased or induced autophagy can reverse these deficits. However, until now, the underlying mechanism of the deficient autophagy has not been clear. Nixon and colleagues have identified a defect in the acidification of the lysosome organelle specifically associated with mutations in PS1 found in FAD. While PS1 mutations have long been associated with increases in Aβ, this paper identifies a function for the holoprotein as a chaperone in the ER. Furthermore, the researchers were able to identify the ATPase complex that is dissociated in PS1 mutants. These important findings could lead to new avenues of therapies that target the ATPase complex by targeting the chaperone function of PS1.