Cytoplasmic Mislocalization of RNA Polymerase II Subunit RPB1 in Alzheimer Disease Is Linked to Pathologic Tau
Open accessAbstract
Abnormal protein accumulation and mislocalization is a general hallmark of Alzheimer disease. Recent data suggest nucleocytoplasmic transport may be compromised by tau in Alzheimer disease. In this context, we have examined the RNA polymerase II subunit RPB1, which is the catalytic subunit that plays a critical role in transcription. Using immunofluorescence staining in control and Alzheimer disease hippocampal tissue, we show that 2 phosphoisoforms of RPB1 mislocalize from the nucleus to the cytoplasm of neurons in Alzheimer disease. The number of neurons with this cytoplasmic mislocalization is correlated with the burden of pathologic tau (AT8-immunopositive neurons). In order to test whether there is a causal relationship between pathologic tau and cytoplasmic RPB1 accumulation, we used the rTg4510 mouse model, which expresses a regulatable pathologic human tau species harboring the P301L mutation. Using immunofluorescence staining on brain tissue from young (2.5-month-old) and aged (8.5- to 10-month-old) rTg4510 mice, we found a tau- and age-dependent increase in cytoplasmic mislocalization of Rpb1. In summary, this study provides evidence that tau induces mislocalization of RPB1 in Alzheimer disease, and since RPB1 is essential for transcription, this raises the possibility that RPB1 mislocalization could lead to fundamental alterations in neuronal health.
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In vitro studies using soluble phospho-tau oligomers find substantial alterations in nuclear-cytoplasmic transport.
“Not only is there clear morphological evidence of nuclear alterations in AD, but also, in vitro studies using soluble phospho-tau oligomers as a perturbant find substantial alterations in nuclear–cytoplasmic transport (e.g., 31, 33, 37, 54).”
From All the Tau We Cannot See (2023) · cites this paper as [31]
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Self-citation
- Authors
- Dickson, J. R., Yoon, H., Frosch, M. P., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Corresponding author
- Hyman, Bradley T
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-05-15
- Volume
- 80
- Issue
- 6
- Pages
- 530-540
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC8177848
- OpenAlex
- W3162299154
- Cited by
- 13
- References
- 24
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 1
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (R25NS065743)
- JPB Foundation
- Alzheimer’s Disease Research Center is funded by the National Institutes of Health (NIH) National Institute on Aging (1P30AG062421-01)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, RNA polymerase II, RPB1, cytoplasmic mislocalization, tau phosphorylation, nuclear transport, transcription, P301L tau mutation, hippocampus
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cytoplasm, Humans, RNA Polymerase II, tau Proteins
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