Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease
Abstract
The p62/sequestosome-1 is a multifunctional protein containing several protein-protein interaction domains. Through these interactions p62 is involved in the regulation of cellular signaling and protein trafficking, aggregation and degradation. p62 protein can bind through its UBA motif to ubiquitinated proteins and control their aggregation and degradation via either autophagy or proteasomes. p62 protein has been reported to be seen in association with the intracellular inclusions in primary and secondary tauopathies, α-synucleinopathies and other neurodegenerative brain disorders displaying inclusions with misfolded proteins. In Alzheimer's disease (AD), p62 protein is associated with neurofibrillary tangles composed primarily of hyperphosphorylated tau protein and ubiquitin. Increasing evidence indicates that p62 has an important role in the degradation of tau protein. The lack of p62 protein expression provokes the tau pathology in mice. Recent studies have demonstrated that the p62 gene expression and cytoplasmic p62 protein levels are significantly reduced in the frontal cortex of AD patients. Decline in the level of p62 protein can disturb the signaling pathways of Nrf2, cyclic AMP and NF-κB and in that way increase oxidative stress and impair neuronal survival. We will review here the molecular and functional characteristics of p62 protein and outline its potential role in the regulation of Alzheimer's pathogenesis.
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Previous studies reported that cortical tubers of infants with TSC-related intractable epilepsy exhibit phospho-tau immunoreactivity in dysmorphic neurons and glial cells, as well as in cellular processes in the neuropil.
“Previous studies have reported that cortical tubers of infants with TSC-related intractable epilepsy exhibit phospho-tau immunoreactivity, in dysmorphic neurons (without frank neurofibrillary tangles) and glial cells, as well as in cellular processes in the neuropil [21].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [21]
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Tuberous sclerosis complex is associated with a novel human tauopathy
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“Abnormal tau has been found in autopsy specimens from children with TSC [21] and in mechanistic experiments in cultured cells and model organisms [2], but the presence and characteristics of a tauopathy in adults with TSC has not been systematically explored.”
Background
- Authors
- Salminen, A., Kaarniranta, K., Haapasalo, A., Hiltunen, M., Soininen, H., & Alafuzoff, I.
- Affiliations
- University of Eastern Finland (FI)
- Uppsala University (SE)
- Corresponding author
- Salminen, Antero
- ORCID
- Venue
- Progress in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 96
- Issue
- 1
- Pages
- 87-95
- ISSN
- 0301-0082 (ISSN-L)
- OpenAlex
- W2022812411
- Cited by
- 153
- References
- 10
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 9 · 2023: 11 · 2022: 10 · 2021: 7 · 2020: 13 · 2019: 17 · 2018: 8 · 2017: 10 · 2016: 12 · 2015: 7 · 2014: 10 · 2013: 18 · 2012: 7
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Progress in Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Academy of Finland
- Kuopio University Hospital (5772708)
- University of Eastern Finland, Kuopio
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- p62/sequestosome 1, Alzheimer's disease, neurofibrillary tangles, autophagy, proteasome, Nrf2 signaling, NF-κB signaling, cAMP signaling, oxidative stress, neurodegeneration, tauopathy, synucleinopathies
- MeSH terms
- Sequestosome-1 Protein, Alzheimer Disease, Animals, Humans, Signal Transduction, tau Proteins, Ubiquitin, Adaptor Proteins, Signal Transducing
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