MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer's disease-related mutants of amyloid β precursor protein and presenilins
Abstract
The death of cholinergic neurons in the cerebral cortex and certain subcortical regions is linked to irreversible dementia relevant to AD (Alzheimer's disease). Although multiple studies have shown that expression of a FAD (familial AD)-linked APP (amyloid β precursor protein) or a PS (presenilin) mutant, but not that of wild-type APP or PS, induced neuronal death by activating intracellular death signals, it remains to be addressed how these signals are interrelated and what the key molecule involved in this process is. In the present study, we show that the PS1-mediated (or possibly the PS2-mediated) signal is essential for the APP-mediated death in a γ-secretase-independent manner and vice versa. MOCA (modifier of cell adhesion), which was originally identified as being a PS- and Rac1-binding protein, is a common downstream constituent of these neuronal death signals. Detailed molecular analysis indicates that MOCA is a key molecule of the AD-relevant neuronal death signals that links the PS-mediated death signal with the APP-mediated death signal at a point between Rac1 [or Cdc42 (cell division cycle 42)] and ASK1 (apoptosis signal-regulating kinase 1).
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In vitro experiments have shown that induced expression of DOCK3 results in attenuated Aβ secretion through regulation of APP degradation.
“In vitro experiments have shown that induced expression of DOCK3 results in attenuated Aβ secretion through regulation of APP degradation (80, 81).”
From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [81]
Cites
Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R. W., Bullock, R., Love, S., Neal, J. W., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61075-2 · Cited by 1,416 · see citing works
A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease
Salloway, S., Sperling, R., Gilman, S., Fox, N. C., Blennow, K., Raskind, M., Sabbagh, M., Honig, L. S., Doody, R., van Dyck, C. H., et al. (2009) · Neurology · doi:10.1212/wnl.0b013e3181c67808 · Cited by 753 · see citing works
A novel mechanism for the regulation of amyloid precursor protein metabolism
Chen, Q., Kimura, H., & Schubert, D. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200110151 · Cited by 63 · see citing works
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Program, T. V. M. V., Bone, W. P., Siewert, K. M., Jha, A., Klarin, D., Damrauer, S. M., Chang, K.-M., Tsao, P. S., Assimes, T. L., Ritchie, M. D., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00773-z · Cited by 41 · see citing works
Thompson, A. P., Bitsina, C., Gray, J. L., von Delft, F., & Brennan, P. E. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100521 · Cited by 21 · see citing works
“In vitro experiments have shown that induced expression of DOCK3 results in attenuated Aβ secretion through regulation of APP degradation (80, 81).”
Background
- Authors
- Tachi, N., Hashimoto, Y., & Matsuoka, M.
- Affiliations
- Tokyo Medical University (JP)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2012-02-13
- Volume
- 442
- Issue
- 2
- Pages
- 413-422
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2015682243
- Cited by
- 20
- References
- 3
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 6 · 2013: 3
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22590247)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Montreal Cognitive Assessment, Alzheimer's disease, neuronal cell death, amyloid precursor protein, presenilin 1, presenilin 2, familial Alzheimer's disease, Rac1, Cdc42, ASK1, apoptosis, cholinergic neurons, signal integration
- MeSH terms
- Alzheimer Disease, Animals, Base Sequence, Carrier Proteins, Humans, Hybrid Cells, Mutation, Nerve Tissue Proteins, Neurons, Neuropeptides, Recombinant Proteins, Signal Transduction, Amyloid beta-Protein Precursor, Cell Death, DNA Primers, Guanine Nucleotide Exchange Factors, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, RNA, Small Interfering, MAP Kinase Kinase Kinase 5, Mutant Proteins, Mice, Rats, Presenilins, Gene Knockdown Techniques
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