The review, led by Evellyn Mayla de Azevedo and Victoria Simões Bernardo working with senior authors Elis Cristina Araujo Eleutherio and Tiago Fleming Outeiro, was conducted as a scoping review under PRISMA guidelines with a protocol registered in advance on the Open Science Framework. The team searched PubMed/MEDLINE and Web of Science for studies published between December 2020 and December 2025, screening 518 unique records. After removing duplicates and excluding studies that did not focus on SOD1 or lacked analyses of protein misfolding and aggregation, 28 studies met all inclusion criteria. The authors organized the evidence by disease type, brain region, type of SOD1 modification, and reported co-pathologies, deliberately separating mechanistic insights from experimental models against direct observations in human neuropathology.

What emerges from this synthesis is a picture of a protein whose fate is governed by its structural integrity. SOD1 functions as a homodimer, with each subunit binding copper and zinc ions, and its stability depends on metal occupancy, post-translational modifications, and intracellular localization. When these regulatory mechanisms falter, the enzyme can shift from cytoprotective to neurotoxic. Analyses of large datasets of ALS-associated missense variants suggest that mutation-induced destabilization is a major determinant of pathogenicity, particularly around the copper-binding sites. Strikingly, 87.1 percent of analyzed ALS-associated SOD1 variants are predicted to disrupt the stability of the homodimer, shifting the equilibrium toward the formation of toxic trimeric species.

Those trimers have taken on new significance. Recent experimental work identified trimeric SOD1 species as critical intermediates linking conformational instability to both intracellular aggregation and intercellular propagation. Introducing trimer-destabilizing mutations markedly reduces aggregation driven by classic ALS variants such as G85R and G93A, while a trimer-stabilizing mutant promotes aggregate formation. Stabilized trimers are also taken up by cells more efficiently, hinting at a mechanism by which misfolded SOD1 might spread from neuron to neuron. Molecular dynamics simulations add another layer: unfolding of the loops surrounding the metal-binding sites changes how SOD1 interacts with the MATH domain of TRAF6, rewiring protein interaction networks implicated in disease. Destabilization need not be genetic, either. Glycation of SOD1 by methylglyoxal increases the formation of stable oligomers while reducing enzymatic activity, and N-terminal acetylation accelerates amyloid assembly more than tenfold without altering the protein’s overall fold.

The most consequential relationships involve other disease-defining proteins. TDP-43, the RNA-binding protein whose cytoplasmic aggregation marks most cases of ALS and a substantial fraction of frontotemporal dementia, has attracted particular scrutiny. Neuropathological studies of human tissue reveal a mutation-dependent pattern: in ALS caused by SOD1 mutations, phosphorylated TDP-43 inclusions are largely absent despite a heavy burden of disordered SOD1 pathology, whereas wild-type misfolded SOD1 and phosphorylated TDP-43 frequently coexist in sporadic and other familial forms. This suggests that mutant SOD1 drives neurodegeneration through mechanisms largely independent of canonical TDP-43 proteinopathy, defining distinct pathological signatures within the ALS spectrum.

Yet the lack of co-localization in tissue does not rule out direct molecular crosstalk. Experimental studies show that TDP-43 can promote the misfolding of endogenous wild-type SOD1 and induce aggregation of a mutant SOD1 reporter, effects that depend on specific tryptophan residues, Trp68 and Trp172 in TDP-43 and Trp32 in SOD1, which mediate cross-seeding between the two proteins. Co-expression of both proteins synergistically promotes axonopathy in animal models. Proteomic analyses reinforce the connection: in a mouse model expressing mutant SOD1, 392 interacting proteins were identified, eleven percent of which are known TDP-43-binding partners, with the shared interactome enriched for ALS-related and other neurodegenerative pathways. Epigenetic studies reveal both shared and divergent signatures, with reduced DNA methylation in corticospinal motor neurons of both SOD1 and TDP-43 mouse models but opposite patterns of hydroxymethylation.

Connections to Alzheimer’s disease run through tau and amyloid biology. Phosphorylation of SOD1 at threonine 40 by the mTORC1 complex suppresses its enzymatic activity, and tau sits upstream of this process by regulating lysosomal mTORC1 signaling. In tau-deficient neurons, SOD1 activity remains abnormally elevated, while re-expression of tau restores regulation. Exposure to amyloid-beta oligomers decreases AKT and mTORC1 signaling, producing a tau-dependent increase in SOD1 activity, and elevated SOD1 activity has been detected in brain tissue from Alzheimer’s patients. Clinically, SOD1 abundance is increased in the cerebrospinal fluid of Alzheimer’s patients and correlates positively with total tau concentrations across three independent cohorts, suggesting that SOD1 dysregulation participates in pathways linked to tau biology and mitochondrial homeostasis.

The relationship with alpha-synuclein proves strikingly context-dependent. In Parkinson’s disease, postmortem tissue from the substantia nigra pars compacta of patients without SOD1 mutations shows widespread alterations in SOD1 post-translational modifications, including marked reductions in glycosylation and enrichment of eight atypical modifications previously associated with structural disorder and aggregation. A mouse model combining reduced copper availability with SOD1 overexpression reproduces these changes, developing SOD1 inclusions in dopaminergic neurons and motor impairment despite an absence of alpha-synuclein pathology. Conversely, in ALS, seed amplification assays detected fibrillar alpha-synuclein species in cerebrospinal fluid from fourteen percent of patients, with positivity highest in the Guamanian ALS-Parkinsonism-dementia complex and markedly lower in familial cases carrying SOD1 or C9orf72 mutations. Perhaps most surprising, in neonatal hypoxic-ischemic encephalopathy, a condition of severe cellular stress rather than a classical neurodegenerative disease, researchers found widespread oxidized and misfolded SOD1 immunoreactivity in neurons and glia alongside aggregated alpha-synuclein, raising the possibility that SOD1 misfolding represents a broader cellular response to neuronal injury.

These converging lines of evidence carry tangible translational weight. SOD1 seeding activity can be detected by real-time quaking-induced conversion assays in postmortem motor cortex and spinal cord at dilutions as high as ten to the minus fifth, in both familial and sporadic ALS, establishing pathological conformers as disease-associated molecular species. Therapeutically, the antisense oligonucleotide tofersen, already approved for SOD1-linked ALS, demonstrated in long-term phase 3 data an approximately 3.4-year extension in event-free survival when started early in faster-progressing patients. A small molecule, PRG-A-04, reduced SOD1 aggregation and extended survival in transgenic mice, while compounds that acetylate lysine residues on fibrillar SOD1 diminish its prion-like propagation. Inhibitors of HDAC6, enhancers of autophagy such as fisetin and ibudilast, and the E3 ubiquitin ligase PJA1 each target different stages of the proteostasis failure that allows misfolded SOD1 to accumulate. The authors caution that whether these co-pathologies reflect direct interactions, cross-seeding, shared stress responses, or independent parallel events remains unresolved, and that standardized detection methods and advanced single-cell and spatial omics approaches will be needed to disentangle cause from consequence. Still, the paradigm is shifting: SOD1 is no longer merely an antioxidant enzyme or a rare genetic culprit, but a potential node in the interconnected protein networks that drive neurodegeneration, and a candidate biomarker and drug target whose relevance may span diseases that medicine has long treated as separate.

Subject of Research: SOD1 misfolding and co-pathology with TDP-43, tau, alpha-synuclein, and amyloid-beta in neurodegenerative disease

Article Title: SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications

Article References: de Azevedo, E. M., Bernardo, V. S., Lima, M. M. S., Eleutherio, E. C. A., & Outeiro, T. F. (2026). SOD1 co-pathologies in the brain: insights from neuropathological evidence and implications. Acta Neuropathologica, 152(1), Article 43. https://doi.org/10.1007/s00401-026-03090-7

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03090-7

Keywords: SOD1, ALS, TDP-43, tau, alpha-synuclein, amyloid-beta, protein aggregation, neurodegeneration, neuropathology, biomarkers, tofersen, proteostasis