. Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a γ-secretase-independent manner. J Neurosci. 2011 Feb 23;31(8):2781-91. PubMed.


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  1. In 2010, Ralph Nixon’s lab published a beautiful study demonstrating the involvement of presenilin-1 (PS1) in autophagy function and lysosome acidification (Lee et al., 2010). They were able to show that certain PS1 mutations, found in familial Alzheimer's disease (AD) cases, lead to the mistargeting of the v-ATPase V0a1 subunit, and thus cause diminished lysosomal protein degradation (see ARF related news story). This current study is a very exciting extension of this work, demonstrating that both PS1 and PS2 are required for the correct functioning of autophagosomal-lysosomal protein degradation and that this PS involvement appears to reach well beyond the inhibition of lysosomal acidification.

    Neely and colleagues use PS1, PS2, and PS1 and 2 knockout cells and PS siRNAs to probe the effects of reduced PS levels on autophagy. They find increased levels of LC3-II, a common marker for mature autophagosomes and decreased phospho-mTOR, normally a key inhibitor of autophagy activation, and conclude that autophagy activity appears elevated. The authors then demonstrate accumulation of EGFP-LC3-positive vacuoles in PS-knockout cells and interpret that as a buildup of autophagosomes. Additionally, they show that this effect is independent of γ-secretase activity of the presenilins. To test if this activated autophagy is, in fact, able to properly degrade long-lived proteins, Neely and colleagues perform a pulse-chase protein degradation assay. Interestingly, they discover that protein degradation is impaired in PS-knockout cells, despite the abundant presence of autophagosomes and apparent markers of autophagy activation. Further experiments indicate that this degradative impairment in PS-knockout cells is neither due to inhibition of the ubiquitin-proteasome system, nor could it be rescued by stimulating autophagy even further, using pharmacological compounds. The authors conclude that presenilins play an important role in regulating autophagosomal-lysosomal protein degradation in a γ-secretase independent manner.

    This study is an exciting step forward in our understanding of the complex machinery that regulates autophagy initiation, elongation, and autophagosomal-lysosomal fusion. It demonstrates that the large protein factories that orchestrate intracellular protein and vesicle sorting may have an important role in the development of neurodegenerative diseases, especially in proteinopathies. Presenilins, previously mostly known for their involvement in amyloid-β pathology of AD, now appear onstage again in a γ-secretase-independent pathway. We think the reduction of beclin-1 in the PS double-knockout cells is particularly interesting: Beclin-1 is a key autophagy-regulating protein with a known involvement in AD (Pickford et al., 2008). Here, Neely and colleagues do not see this reduction in the short-term siRNA experiments, and they propose that in long-term disease stages and stably transfected cell lines, loss of PS function could cause the accumulation of undegradable autophagosomes and reduced beclin-1 levels. This is in good agreement with data from our laboratory, where the inhibition of autophagosomal-lysosomal fusion led to decreased levels of beclin-1, and beclin-1 was indeed reduced in brains of sporadic AD patients (Jaeger et al., 2010). There, we showed in vitro and in vivo that beclin-1 can be reduced at the same time while LC3-II accumulates, similar to the findings of Neely and coauthors after PS-knockout.

    A complex protein network appears to exist that regulates autophagy initiation and autophagosomal-lysosomal fusion, and this complex might involve both, presenilins and beclin-1. Recent publications have successfully mapped interaction partners for PS1 (Wakabayashi et al., 2009) and, while not directly detecting beclin-1, found many proteins involved in membrane trafficking. One particularly interesting protein is VCP/p97, a protein implicated in autophagy regulation, protein degradation, and mutations that are associated with neurodegenerative diseases (Ju et al., 2009; Hirabayashi et al., 2001). It will be very exciting to further investigate the protein machinery that controls the assembly of intracellular degradation and trafficking vacuoles. The identification of novel proteins and protein interactions, such as in this study, will allow us to enhance our understanding of neurological disorders that appear to suffer from two seemingly exclusive features: too much autophagy activation and too little protein turnover.


    . Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010 Jun 25;141(7):1146-58. PubMed.

    . 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.

    . Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS One. 2010;5(6):e11102. PubMed.

    . Analysis of the gamma-secretase interactome and validation of its association with tetraspanin-enriched microdomains. Nat Cell Biol. 2009 Nov;11(11):1340-6. PubMed.

    . Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol. 2009 Dec 14;187(6):875-88. PubMed.

    . VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration. Cell Death Differ. 2001 Oct;8(10):977-84. PubMed.

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  1. Evidence Piles Up for Presenilins’ Role in Autophagy