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

Yevgen Chornenkyy, David W. Fardo, Peter T. Nelson

Research output: Contribution to journalReview articlepeer-review

43 Scopus citations


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.

Original languageEnglish
Pages (from-to)993-1007
Number of pages15
JournalLaboratory Investigation
Issue number7
StatePublished - Jul 1 2019

Bibliographical note

Funding Information:
Acknowledgements We are very grateful to the research volunteers, clinicians, and staff for their hard work. Grant support was received via National Institutes of Health grants P30 AG028303, R01 AG042475, R01 AG057187, and R21 AG050146.

Publisher Copyright:
© 2019, United States & Canadian Academy of Pathology.

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology


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