title: 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.
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California 92697-4545, USA.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Neely
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000172:deficiency / Q000502:physiology*; D053766:Presenilin-2 / Q000172:deficiency / Q000502:physiology*; D011506:Proteins / Q000378:metabolism
chemical_list: D053764:Presenilin-1; D053766:Presenilin-2; D011506:Proteins; D053829:Amyloid Precursor Protein Secretases