Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic accumulation of phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathological hallmark of most ALS cases. While ALS has traditionally been viewed as a disease confined to the brain, spinal cord and motor nerves, recent studies have reported pTDP-43 pathology in multiple other tissues (skeletal and cardiac muscle, skin, minor salivary glands, gastrointestinal tract and lymph nodes), referred to as peripheral pathology. The detection of pTDP-43 beyond the nervous system suggests that ALS-associated TDP-43 proteinopathy may be more widespread than previously recognized and raises fundamental questions regarding the spatial and temporal landscape of ALS pathology. Peripheral pTDP-43 accumulation may reflect a systemic biological susceptibility affecting multiple tissues, propagation of pathological TDP-43 species between anatomical compartments, or a combination of both mechanisms. While its biological significance is yet to be determined, the presence of pTDP-43 in peripheral tissues broadens the current conceptual framework of ALS. It may also provide new opportunities for pathology-based biomarkers, therapeutic monitoring, and mechanistic studies aimed at understanding disease initiation and progression. However, current evidence is derived from small and methodologically heterogeneous cohorts, and peripheral pTDP-43 pathology is not restricted to ALS, emphasizing the need for larger standardized studies.
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BibTeX
@article{codron2026peripheral,
title = {{Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy}},
author = {Philippe Codron and Marion Miranda and Maelle Garnier and Shiyang He and Julien Gouju and Julien Cassereau and Pascal Leblanc and Franck Letournel},
journal = {Acta Neuropathologica},
year = {2026},
month = sep,
doi = {10.1007/s00401-026-03086-3},
url = {https://hal.science/hal-05790506v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy
AU - Philippe Codron
AU - Marion Miranda
AU - Maelle Garnier
AU - Shiyang He
AU - Julien Gouju
AU - Julien Cassereau
AU - Pascal Leblanc
AU - Franck Letournel
PY - 2026
DA - 2026/09/15
JO - Acta Neuropathologica
DO - 10.1007/s00401-026-03086-3
UR - https://hal.science/hal-05790506v1
AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic accumulation of phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathological hallmark of most ALS cases. While ALS has traditionally been viewed as a disease confined to the brain, spinal cord and motor nerves, recent studies have reported pTDP-43 pathology in multiple other tissues (skeletal and cardiac muscle, skin, minor salivary glands, gastrointestinal tract and lymph nodes), referred to as peripheral pathology. The detection of pTDP-43 beyond the nervous system suggests that ALS-associated TDP-43 proteinopathy may be more widespread than previously recognized and raises fundamental questions regarding the spatial and temporal landscape of ALS pathology. Peripheral pTDP-43 accumulation may reflect a systemic biological susceptibility affecting multiple tissues, propagation of pathological TDP-43 species between anatomical compartments, or a combination of both mechanisms. While its biological significance is yet to be determined, the presence of pTDP-43 in peripheral tissues broadens the current conceptual framework of ALS. It may also provide new opportunities for pathology-based biomarkers, therapeutic monitoring, and mechanistic studies aimed at understanding disease initiation and progression. However, current evidence is derived from small and methodologically heterogeneous cohorts, and peripheral pTDP-43 pathology is not restricted to ALS, emphasizing the need for larger standardized studies.
SN - 0001-6322
SN - 1432-0533
ER -