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UCI MIND Scientists uncover presenilin function

By February 24, 2011In the News

UCI MIND graduate student Kara Neely, and Professors Green and LaFerla have discovered a key role for presenilin, a protein involved in the production of amyloid-beta, which forms the plaques in Alzheimer’s disease.  In a study published in the February 23rd edition of the Journal of Neuroscience, the research team show that presenilin plays an integral role in the way that cells, including neurons, dispose of misfunctioning and broken proteins.  The accumulation of misfunctioning and broken proteins inside cells is thought to contribute to many neurodegenerative diseases, as well as to the aging process itself.  This research highlights an important function of the presenilins, in addition to their role in producing the toxic amyloid-beta peptide, and may contribute to the disease process itself.

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

Kara M. Neely, Kim N. Green, and Frank M. LaFerla

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.