Journal Article (Review Article)

DZNE-2026-01028

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications.

de Azevedo, E. M. ; Bernardo, V. S. ; Lima, M. M. S. ; Eleutherio, E. C. A. ; Outeiro, T. F. (Last author)DZNE*

2026
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-026-03090-7

Abstract: Superoxide dismutase 1 (SOD1), originally regarded as an antioxidant enzyme, is now recognized as a multifunctional protein whose conformational instability and aggregation contribute to neurodegeneration. The emerging evidence suggests that SOD1 pathology extends beyond amyotrophic lateral sclerosis, supporting a role in multiple neurodegenerative diseases. This review summarizes current neuropathological evidence of SOD1 co-pathologies in the human brain, with particular emphasis on its associations with TAR DNA-binding protein 43 (TDP-43), tau, alpha-synuclein, amyloid-β, and other aggregation-prone proteins. We examine the distribution of pathological SOD1 species across neurodegenerative diseases, their coexistence in affected brain regions, and potential mechanisms underlying these interactions, including oxidative stress, impaired proteostasis, aberrant phase separation, and cross-seeding. We also discuss emerging observations of SOD1 pathology in neurological conditions beyond classical neurodegenerative diseases, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury. Collectively, the available evidence supports a shift from viewing SOD1 as a disease-specific protein to considering it a potential participant in interconnected proteopathic networks. Although the functional significance of SOD1 co-pathologies remains incompletely understood, elucidating the molecular basis of aggregation may provide new insights into disease onset and progression, improving our understanding of neurodegenerative mechanisms, and facilitating the development of biomarkers and the identification of therapeutic targets across diverse proteinopathies.

Keyword(s): Humans (MeSH) ; Superoxide Dismutase-1: metabolism (MeSH) ; Brain: pathology (MeSH) ; Brain: metabolism (MeSH) ; Neurodegenerative Diseases: pathology (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Animals (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; ALS ; Co-pathologies ; FTD ; Neuropathology ; Protein aggregation ; Superoxide Dismutase-1 ; SOD1 protein, human

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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