Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a γ-secretase-independent manner

Abstract

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. Copyright © 2011 the authors.