mutant FUS effects split between motor-neuron intrinsic stress and glial/NMJ in…

Mechanistic description

mutant FUS effects split between motor-neuron intrinsic stress and glial/NMJ inflammatory signaling should produce a measurable proximal phenotype before late disease pathology. The decisive test is isogenic motor-neuron, astrocyte, and microglia chimeric co-cultures with NMJ formation and denervation readouts.

Mechanism / pathway

FUS
→
neurodegeneration

Evidence for (6)

NMJ denervation study identified myeloid cell involvement; cell-autonomous vs. non-cell-autonomous contributions of FUS mutations to NMJ pathology were not separated in the experimental design.

The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis
Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain.

PMID:35640764 2022 J Control Release
SARS-CoV-2, aging, and Post-COVID-19 neurodegeneration.

PMID:36458986 2023 J Neurochem
Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS.

PMID:40970514 2025 Aging Cell
Homozygous ALS-linked FUS P525L mutations cell- autonomously perturb transcriptome profile and chemoreceptor signaling in human iPSC microglia.

PMID:35120624 2022 Stem Cell Reports
Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia.

PMID:34831228 2021 Cells

Evidence against (1)

co-culture systems can exaggerate glial effects and underrepresent muscle and peripheral immune contributions

The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis

Evidence matrix

6 supporting 1 contradicting

86% supporting

Supporting

NMJ denervation study identified myeloid cell involvement; cell-autonomous vs. non-cell-autonomous contributions of FUS mutations to NMJ pathology were not separated in the experimental design. The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis
Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain. PMID:35640764 · 2022 · J Control Release
SARS-CoV-2, aging, and Post-COVID-19 neurodegeneration. PMID:36458986 · 2023 · J Neurochem
Prematurely Aged Human Microglia Exhibit Impaired Stress Response and Defective Nucleocytoplasmic Shuttling of ALS Associated FUS. PMID:40970514 · 2025 · Aging Cell
Homozygous ALS-linked FUS P525L mutations cell- autonomously perturb transcriptome profile and chemoreceptor signaling in human iPSC microglia. PMID:35120624 · 2022 · Stem Cell Reports
Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia. PMID:34831228 · 2021 · Cells

Contradicting

co-culture systems can exaggerate glial effects and underrepresent muscle and peripheral immune contributions The CCL2-CCR2 axis drives neuromuscular denervation in amyotrophic lateral sclerosis

Cite this hypothesis

Citation

etl-backfill (2026). mutant FUS effects split between motor-neuron intrinsic stress and glial/NMJ in…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-f90159a23e

BibTeX

@misc{scidex_hypothesis_hf90159a,
  title        = {mutant FUS effects split between motor-neuron intrinsic stress and glial/NMJ in…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-f90159a23e},
  note         = {SciDEX artifact hypothesis:h-f90159a23e}
}