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Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy
Open accessAbstract
We review the literature on Tau and TDP-43 proteinopathies in aged human brains and the relevant underlying pathogenetic cascades. Complex interacting pathways are implicated in Alzheimer's disease and related dementias (ADRD), wherein multiple proteins tend to misfold in a manner that is "reactive," but, subsequently, each proteinopathy may contribute strongly to the clinical symptoms. Tau proteinopathy exists in brains of individuals across a broad spectrum of primary underlying conditions-e.g., developmental, traumatic, and inflammatory/infectious diseases. TDP-43 proteinopathy is also expressed in a wide range of clinical disorders. Although TDP-43 proteinopathy was first described in the central nervous system of patients with amyotrophic lateral sclerosis (ALS) and in subtypes of frontotemporal dementia (FTD/FTLD), TDP-43 proteinopathy is also present in chronic traumatic encephalopathy, cognitively impaired persons in advanced age with hippocampal sclerosis, Huntington's disease, and other diseases. We list known Tau and TDP-43 proteinopathies. There is also evidence of cellular co-localization between Tau and TDP-43 misfolded proteins, suggesting common pathways or protein interactions facilitating misfolding in one protein by the other. Multiple pleiotropic gene variants can alter risk for Tau or TDP-43 pathologies, and certain gene variants (e.g., APOE ε4, Huntingtin triplet repeats) are associated with increases of both Tau and TDP-43 proteinopathies. Studies of genetic risk factors have provided insights into multiple nodes of the pathologic cascades involved in Tau and TDP-43 proteinopathies. Variants from a specific gene can be either a low-penetrant risk factor for a group of diseases, or alternatively, a different variant of the same gene may be a disease-driving allele that is associated with a relatively aggressive and early-onset version of a clinically and pathologically specific disease type. Overall, a complex but enlightening paradigm has emerged, wherein both Tau and TDP-43 proteinopathies are linked to numerous overlapping upstream influences, and both are associated with multiple downstream pathologically- and clinically-defined deleterious effects.
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“tau pathology is a defining feature not only of Alzheimer's disease (AD) but also of almost half of FTD cases (typically those without TDP-43 pathology)”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chornenkyy et al. 2019
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“Age-dependent neurodegenerative disorders are clinically diverse but exhibit significant comorbidity and heterogeneous pathology both within and across disorders”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chornenkyy et al. 2019
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Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
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Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050
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Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report
Nelson, P. T., Dickson, D. W., Trojanowski, J. Q., Jack, C. R., Boyle, P. A., Arfanakis, K., Rademakers, R., Alafuzoff, I., Attems, J., Brayne, C., et al. (2019) · Brain · doi:10.1093/brain/awz099 · Cited by 1,547
Self-citationThe role of TDP-43 mislocalization in amyotrophic lateral sclerosis
Suk, T. R., & Rousseaux, M. W. C. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00397-1 · Cited by 483
Prevalence and clinical phenotype of quadruple misfolded proteins in older adults
Karanth, S., Nelson, P. T., Katsumata, Y., Kryscio, R. J., Schmitt, F. A., Fardo, D. W., Cykowski, M. D., Jicha, G. A., Van Eldik, L. J., & Abner, E. L. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.1741 · Cited by 206
Self-citationNelson, P. T., Brayne, C., Flanagan, M. E., Abner, E. L., Agrawal, S., Attems, J., Castellani, R. J., Corrada, M. M., Cykowski, M. D., Di, J., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02444-1 · Cited by 187
Self-citationLATE-NC staging in routine neuropathologic diagnosis: an update
Nelson, P. T., Lee, E. B., Cykowski, M. D., Alafuzoff, I. I., Arfanakis, K., Attems, J., Brayne, C., Corrada, M. M., Dugger, B. N., Flanagan, M. E., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02524-2 · Cited by 189
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Metadata
- Authors
- Chornenkyy, Y., Fardo, D. W., & Nelson, P. T.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Nelson, Peter T.
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 99
- Issue
- 7
- Pages
- 993-1007
- ISSN
- 0023-6837 (ISSN-L)
- PMC
- PMC6609463
- OpenAlex
- W2912060415
- Cited by
- 93
- References
- 206
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 12 · 2023: 10 · 2022: 17 · 2021: 10 · 2020: 15 · 2019: 7
- FWCI
- 1.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P30 AG028303)
- National Institute on Aging (P30AG028383, R01AG057187, R21AG050146, R56AG057191, R01AG042475, R01AG028303, R01AG061111)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TDP-43 proteinopathy, protein misfolding, Alzheimer's disease and related dementias, frontotemporal dementia, amyotrophic lateral sclerosis, chronic traumatic encephalopathy, hippocampal sclerosis, Huntington's disease, pleiotropy, APOE ε4, protein colocalization, brain aging
- MeSH terms
- Animals, Humans, Tauopathies, TDP-43 Proteinopathies, Genetic Pleiotropy
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