Cited by 93Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchDementia and Cognitive Impairment Research

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Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy

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Chornenkyy, Yevgen, Fardo, David W., Nelson, Peter T.·2019·Laboratory Investigation

DOI 10.1038/s41374-019-0196-yPMC PMC6609463

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Abstract

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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Authors: Chornenkyy, Y., Fardo, D. W., & Nelson, P. T.
Affiliations: University of Kentucky (US)
Corresponding author: Nelson, Peter T.
ORCID: Chornenkyy, Yevgen
Fardo, David W.
Nelson, Peter T.
Venue: Laboratory Investigation
Publisher: Elsevier BV
Published: 2019-07
Volume: 99
Issue: 7
Pages: 993-1007
ISSN: 0023-6837 (ISSN-L)
DOI: 10.1038/s41374-019-0196-y
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1290 d)
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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Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy

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