{
  "id": 4580857,
  "title": "Characterizing shared and distinctive molecular phenotypes across motor regions in ALS with and without TDP-43 pathology in a veteran cohort",
  "url": "https://urgent.news/2026/08/30/characterizing-shared-and-distinctive-molecular-phenotypes-across",
  "topic": "science",
  "section": "Science",
  "published": "2026-08-30T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747944v1?rss=1"
  },
  "original_language": "en",
  "account": "Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition marked by the gradual deterioration and loss of upper and lower motor neurons. While the ultimate outcome is paralysis, neuronal dysfunction may occur prior to cell demise, suggesting that vulnerable neurons activate stress-adaptive mechanisms that enable survival despite impaired function. Cellular senescence is one such persistent stress response and has been increasingly linked to neurodegenerative diseases, including those with TDP-43 pathology. In this study, researchers examined whether senescence-associated molecular states exist in vulnerable motor neurons in ALS and whether these states vary by anatomical region and phosphorylated TDP-43 (pTDP-43) status. Postmortem samples were collected from the Department of Veterans Affairs Biorepository Brain Bank, including motor cortex, cervical spinal cord, and lumbar spinal cord from ALS patients classified as either pTDP-43-positive or pTDP-43-negative, as well as non-ALS controls. Targeted bulk transcriptomic analysis was combined with GeoMx Digital Spatial Profiling of individual motor neurons to identify disease-, region-, and pathology-associated molecular patterns while maintaining anatomical context. Across all ALS cases, alterations in pathways related to cell-cycle regulation, RNA processing, mitochondrial function, proteostasis, inflammation, and synaptic signaling were observed. These signatures differed based on anatomical region and pTDP-43 status, indicating significant variability in the molecular response to ALS pathology. However, both ALS groups shared convergent proteomic and transcriptomic features linked to cellular senescence. These results identify senescence-associated molecular states in vulnerable neuronal populations in ALS and support the notion that persistent stress adaptation may allow neuronal survival while contributing to progressive cellular dysfunction. The spatially resolved analysis connects neuronal phenotype to anatomical and pathological context and suggests that senescence-associated pathways could be therapeutic targets in ALS.",
  "summary": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive dysfunction and loss of upper and lower motor neurons. Although motor neuron degeneration ultimately drives paralysis, neuronal dysfunction may precede cell death by a prolonged interval, suggesting that vulnerable neurons engage stress-adaptive programs that permit survival despite impaired…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}