Ubiquilin regulates presenilin endoproteolysis and modulates γ-secretase components, Pen-2 and nicastrin
Open accessAbstract
Mutations in presenilin proteins (PS1 and PS2) lead to early-onset Alzheimer's disease. PS proteins are endoproteolytically cleaved into two main fragments: the NTF (PS N-terminal fragment) and the CTF (PS C-terminal fragment). The two fragments are believed to constitute the core catalytic enzyme activity called γ-secretase, which is responsible for cleaving β-amyloid precursor protein to release Aβ. Thus, studying factors that modulate PS fragment levels could provide important information about γ-secretase. Previously, we demonstrated that the protein, ubiquilin-1, interacts both in vivo and in vitro with PS and that overexpression of ubiquilin-1 or -2 leads to increased accumulation of full-length PS proteins. Using wild-type HEK-293 cells (human embryonic kidney 293 cells) and PS-inducible cells, we now show that overexpression of either ubiquilin-1 or -2 decreases the PS NTF and CTF levels. Conversely, siRNA (small interfering RNA)-mediated knockdown of ubiquilin-1 and -2 proteins increased the PS NTF and CTF levels. We considered that ubiquilin might alter PS fragment accumulation by acting as a shuttle factor escorting PS fragments to the proteasome for degradation. However, through proteasome inhibition studies, we show that this does not occur. Instead, our results suggest that ubiquilin regulates PS fragment production. We also examined whether other components of the γ-secretase complex are affected by ubiquilin expression. Interestingly, overexpression of ubiquilin resulted in a decrease in Pen-2 and nicastrin levels, two essential components of the γ-secretase complex. In contrast, knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels. Finally, we show that inhibition of the proteasome results in decreased PS fragment production and that reversal of proteasome inhibition restores PS fragment production, suggesting that the proteasome may be involved in PS endoproteolysis. These studies implicate ubiquilin as an important factor in regulating PS biogenesis and metabolism.
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Presenilin ubiquitination can cause reduction of endoproteolisis, which in turn reduces the formation of two fragments (presenilin N- and C-terminal fragments) that are essential for the γ-secretase activity.
“Moreover, there is evidence suggesting that presenilin ubiquitination can cause reduction of endoproteolisis, which in turn reduces the formation of two fragments (presenilin N- and C-terminal fragments) that are essential for the γ-secretase activity.51”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [51]
Presenilin proteins can be ubiquitinated.
“In previous studies it has been shown that presenilin proteins can be ubiquitinated.51, 52”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [51]
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APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease
Vélez, J. I., Lopera, F., Sepulveda-Falla, D., Patel, H. R., Johar, A. S., Chuah, A., Tobón, C., Rivera, D., Villegas, A., Cai, Y., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.177 · Cited by 111 · see citing works
Duggan, S. P., Yan, R., & McCarthy, J. V. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.03.008 · Cited by 10 · see citing works
- Authors
- Massey, L. K., Mah, A. L., & Monteiro, M. J.
- Affiliations
- University of Maryland, Baltimore (US)
- ORCID
- Monteiro, Mervyn J.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2005-10-25
- Volume
- 391
- Issue
- 3
- Pages
- 513-525
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1276952
- OpenAlex
- W2038114557
- Cited by
- 66
- References
- 56
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 6 · 2015: 3 · 2014: 5 · 2013: 6 · 2012: 1
- FWCI
- 5.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG016839, AG016839)
- National Institute of General Medical Sciences (GM066287, R01GM066287)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- UBQLN1, UBQLN2, presenilin, gamma-secretase, Pen-2, nicastrin, proteasome, Alzheimer's disease, protein degradation, siRNA knockdown
- MeSH terms
- Autophagy-Related Proteins, Carrier Proteins, Cell Line, Humans, Membrane Glycoproteins, Membrane Proteins, Peptide Fragments, Endopeptidases, Ubiquitins, Gene Expression Regulation, Enzymologic, Aspartic Acid Endopeptidases, Cell Cycle Proteins, RNA Interference, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, Presenilin-1, Presenilin-2, Amyloid Precursor Protein Secretases
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