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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Comments
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.
Nixon and colleagues show the involvement of PS1 in autophagy/lysosomal function, and indicate that PS1 mutations in familial AD cause its impairment.
We believe that the autophagic/lysosomal pathway is a key therapeutic target, and it is important to investigate further if improving its function would be beneficial for decreasing amyloid-β production in vivo.
New York University School of Medicine/Nathan Kline Institute
The results in Jaeger et al. reinforce previous work from their lab (Pickford et al., 2008) showing that autophagy is a significant APP turnover pathway that can be strongly upregulated in cells. During autophagy induction, APP levels decreased somewhat more than Aβ levels, consistent with earlier data that Aβ is generated during autophagy and that efficient lysosomal proteolysis is needed to prevent the intracellular buildup of Aβ in autophagic vacuoles and lysosomes seen in AD. The authors also show that the block in autophagosome clearance in AD and AD mouse models can be exacerbated by beclin deficiency. This may be due to the impairment of early autophagy steps of autophagosome formation, which require beclin, as proposed in the paper, and it could also reflect interference with beclin-dependent late endosome functions, disturbances of which are known to disrupt amphisome formation and clearance through autophagy (1). Interestingly, the resultant buildup of APP and β-CTF in endosomal-related compartments is reminiscent of the conditions that develop in Down syndrome, where it has been shown that APP duplication, through elevations of β-CTF, accelerates endocytosis (2). This creates more substrate traffic to lysosomes, interferes with endosome functions (2,3), and we suspect, also impairs autophagic turnover. These new investigations add to mounting evidence that disruption of lysosomal clearance mechanisms may be a critical factor in AD pathogenesis.
References:
Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerød L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol. 2007 Nov 5;179(3):485-500. PubMed.
Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, Nixon RA. Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1630-5. Epub 2009 Dec 28 PubMed.
Cataldo AM, Mathews PM, Boiteau AB, Hassinger LC, Peterhoff CM, Jiang Y, Mullaney K, Neve RL, Gruenberg J, Nixon RA. Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects. Am J Pathol. 2008 Aug;173(2):370-84. PubMed.
View all comments by Ralph NixonStanford University Medical School
The study by Nixon and colleagues is an absolutely gorgeous paper. It is cell biology at its best. It is interesting that our studies manipulating beclin-1 arrive at a very similar pathology as the lack of presenilin, both in vivo and in cell culture, causing an abnormal accumulation of lysosomes and autolysosomes (see also Pickford et al., 2008). Indeed, beclin-1 may have a role not only in the initiation of autophagy, but as an increasing number of studies suggest, in vesicle trafficking as well. Whether beclin-1 and presenilins interact at some level will be interesting to explore in the future.
However, we could have a friendly debate about whether autophagy really requires presenilin as stated in the title, since the study does not actually manipulate the autophagy process. Rather, it interferes with the final degradative step and shows very nicely that presenilins are necessary for lysosomal degradation.
If autophagy is the process of manufacturing garbage bags, filling them with trash, and hauling them to the dump, lysosomal degradation would be the incineration of the trash-filled bags. For the incinerator to run, you need fuel and pipes that bring the fuel into the incinerator (the ATPase). If the incinerator does not run, you will naturally accumulate the bags filled with trash, but it would not follow that garbage bag production is impaired.
Furthermore, it is likely that endosomal trafficking and multivesicular bodies are equally affected by lysosomal degradation, but the paper does not discuss these possibilities.
References:
Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest. 2008 Jun;118(6):2190-9. PubMed.
New York University School of Medicine/Nathan Kline Institute
Reply to comment by Tony Wyss-Coray
Since its very early descriptions, autophagy has been defined as the lysosomal digestion of a cell’s own cytoplasmic material and not simply the sequestration of these components. Implied by this definition, and generally accepted in the autophagy field, is the central concept that lysosomal proteolysis is required to complete autophagy. This is a critical point, especially because autophagy failure in disease states, as measured by the diminished turnover of specific autophagy substrates, can result from failure of substrate sequestration, autophagosome formation, fusion of autophagosomes with a lysosome, or digestion of the substrate. Distinguishing which step in autophagy is defective in different neurodegenerative diseases has become important and usually involves evaluating not only autophagosome formation, but also autophagic flux, which reflects the balance between substrate sequestration and proteolytic clearance (1). Narrowly defining autophagy as only the sequestration step during autophagy, as proposed by Tony Wyss-Coray, does not recognize the well-accepted key role of the lysosome in this self-digestion process.
Tony points out that our results imply, but do not show, that cargoes delivered to lysosomes by endocytosis should also be affected by lysosomal failure. Indeed, we present data in our paper demonstrating that lysosomal turnover of endosomal substrates is decreased, as one might predict. Thus, in addition to being required for autophagy, presenilin-1 is required for the turnover of endosomal substrates.
References:
Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 2010 Jul;13(7):805-11. PubMed.
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