Galectin-3 as Damage-Sensor Scaffold for Multimeric Cross-Seeding at Compromise…

Mechanistic description

Galectin-3’s carbohydrate recognition domain binds exposed glycans on ruptured endolysosomal membranes while its intrinsically disordered N-terminus provides a phase-separated condensation surface that recruits aggregation-prone proteins (Aβ42, α-synuclein, TDP-43) into localized high-concentration environments favoring cross-nucleation.

Mechanism / pathway

LGALS3
→
neurodegeneration

Evidence for (5)

ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.

PMID:39605053 2024 Acta Neuropathol Commun
ALS-associated TDP-43 aggregates drive innate and adaptive immune cell activation.

PMID:40520109 2025 iScience
Towards a TDP-43-Based Biomarker for ALS and FTLD.

PMID:29460270 2018 Mol Neurobiol
TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation.

PMID:40654715 2025 bioRxiv
Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.

PMID:40602832 2025 Life Sci Alliance

Evidence against (3)

Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles.

PMID:32048886 2021 Autophagy
Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders.

PMID:33535376 2021 Int J Mol Sci
Wallerian degeneration: the innate-immune response to traumatic nerve injury.

PMID:21878125 2011 J Neuroinflammation

Evidence matrix

5 supporting 3 contradicting

63% supporting

Supporting

ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice. PMID:39605053 · 2024 · Acta Neuropathol Commun
ALS-associated TDP-43 aggregates drive innate and adaptive immune cell activation. PMID:40520109 · 2025 · iScience
Towards a TDP-43-Based Biomarker for ALS and FTLD. PMID:29460270 · 2018 · Mol Neurobiol
TDP-43 toxic gain of function links ALS, FTD and Alzheimer's Disease through splicing dysregulation. PMID:40654715 · 2025 · bioRxiv
Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models. PMID:40602832 · 2025 · Life Sci Alliance

Contradicting

Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. PMID:32048886 · 2021 · Autophagy
Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders. PMID:33535376 · 2021 · Int J Mol Sci
Wallerian degeneration: the innate-immune response to traumatic nerve injury. PMID:21878125 · 2011 · J Neuroinflammation

Cite this hypothesis

Citation

etl-backfill (2026). Galectin-3 as Damage-Sensor Scaffold for Multimeric Cross-Seeding at Compromise…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/hyp-sda-2026-04-01-gap-9137255b-1

BibTeX

@misc{scidex_hypothesis_hypsda20,
  title        = {Galectin-3 as Damage-Sensor Scaffold for Multimeric Cross-Seeding at Compromise…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/hyp-sda-2026-04-01-gap-9137255b-1},
  note         = {SciDEX artifact hypothesis:hyp-sda-2026-04-01-gap-9137255b-1}
}