RT Journal Article
SR Electronic
T1 Presenilin Is Necessary for Efficient Proteolysis through the Autophagy–Lysosome System in a γ-Secretase-Independent Manner
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2781
OP 2791
DO 10.1523/JNEUROSCI.5156-10.2010
VO 31
IS 8
A1 Kara M. Neely
A1 Kim N. Green
A1 Frank M. LaFerla
YR 2011
UL http://www.jneurosci.org/content/31/8/2781.abstract
AB 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.