Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 33, Pages 13416-13421Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206786109
Keywords
trafficking; neurodegeneration; ubiquitin-associated domain; ubiquitin-like domain
Categories
Funding
- National Institutes of Health [R21AG031948, F30AG030878]
- Jean C. and William D. Willis Neuroscience Research Endowment
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The pathogenesis of Alzheimer's disease (AD) is associated with proteolytic processing of the amyloid precursor protein (APP) to an amyloidogenic peptide termed A beta. Although mutations in APP and the secretase enzymes that mediate its processing are known to result in familial forms of AD, the mechanisms underlying the more common sporadic forms of the disease are still unclear. Evidence suggests that the susceptibility of APP to amyloidogenic processing is related to its intracellular localization, and that secretase-independent degradation may prevent the formation of cytotoxic peptide fragments. Recently, single nucleotide polymorphisms in the UBQLN1 gene have been linked to late-onset AD, and its protein product, ubiquilin-1, may regulate the maturation of full-length APP. Here we show that ubiquilin-1 inhibits the maturation of APP by sequestering it in the early secretory pathway, primarily within the Golgi apparatus. This sequestration significantly delayed the proteolytic processing of APP by secretases and the proteasome. These effects were mediated by ubiquilin-1-stimulated K63-linked polyubiquitination of lysine 688 in the APP intracellular domain. Our results reveal the mechanistic basis by which ubiquilin-1 regulates APP maturation, with important consequences for the pathogenesis of late-onset AD.
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