Presenilin Is Necessary for Efficient Proteolysis through the Autophagy-Lysosome System in a -Secretase-Independent Manner

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2011; 31(8):2781-91. DOI: 10.1523/JNEUROSCI.5156-10.2010
Source: PubMed


Presenilins are ubiquitous, intramembrane proteins that function in Alzheimer's disease (AD) as the catalytic component of the γ-secretase complex. Familial AD mutations in presenilin are known to exacerbate lysosomal pathology. Hence, we sought to elucidate the function endogenous, wild-type presenilins play in autophagy-mediated protein degradation. We report the finding that genetic deletion or knockdown of presenilins alters many autophagy-related proteins demonstrating a buildup of autophagosomes, indicative of dysfunction in the system. Presenilin-deficient cells inefficiently clear long-lived proteins and fail to build up autophagosomes when challenged with lysosomal inhibitors. Our studies further show that γ-secretase inhibitors do not adversely impact autophagy, indicating that the role of presenilins in autophagy is independent of γ-secretase activity. Based on our findings, we conclude that endogenous, wild-type presenilins are necessary for proper protein degradation through the autophagosome-lysosome system by functioning at the lysosomal level. The role of presenilins in autophagy has many implications for its function in neurological diseases such as AD.

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Available from: Kim N Green, Dec 01, 2014
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    • "Excessive generation of A␤ in AD brain cells is also driven by increased levels of the ␥-secretase complex within autophagosomes. However, there is also a report to suggest that presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a ␥-secretase-independent manner [176]. eA␤ can also be cleared from the brain through interaction with lipoprotein receptors [177]. "
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    • "Nevertheless, Coen et al. demonstrated that the calcium loading of lysosome in PS1−/− or PS1−/−/PS2−/− cells was significantly less than wild type cells, which could be rescued by PS1 mutant without γ-secretase activity, indicating the γ-secretase-independent property. Given that PS1 itself could act as ER Ca2+ leak channels, they proposed that the accumulation of autophagic vacuoles often observed in AD could be interpreted by impaired PS1-related calcium abnormality [164-166]. "
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    • "Presenilins, the catalytic subunits of the γ-secretase complex [99,100] have directly been linked to lysosomal biogenesis and function [101,102]. Numerous studies have proposed a requirement or presenlins for lysosomal function independent of its role in the γ-secretase complex, although the precise molecular mechanism remains to be determined [9,103-105]. Remarkably, presenilins seem to play a role in lysosomal Ca2+ storage, suggesting a potential molecular mechanism [9,105]. "
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