{
  "task": 1581,
  "analysis": "SST_PLTS neurodegeneration leading-edge gene extraction",
  "source_enrichment": "KEGG_2021_Human: Pathways of neurodegeneration (padj=0.0147)",
  "leading_edge_genes": [
    "NOS1",
    "UCHL1",
    "PRNP",
    "GRIA3",
    "CALM2",
    "CHRM3"
  ],
  "n_genes": 6,
  "category_breakdown": {
    "Nitrosative/oxidative stress": [
      "NOS1"
    ],
    "Ubiquitin-proteasome / proteostasis": [
      "UCHL1"
    ],
    "Protein aggregation / misfolding": [
      "PRNP"
    ],
    "Excitotoxicity": [
      "GRIA3"
    ],
    "Calcium signaling dysregulation": [
      "CALM2",
      "CHRM3"
    ]
  },
  "category_counts": {
    "Nitrosative/oxidative stress": 1,
    "Ubiquitin-proteasome / proteostasis": 1,
    "Protein aggregation / misfolding": 1,
    "Excitotoxicity": 1,
    "Calcium signaling dysregulation": 2
  },
  "key_finding": "NOT primarily mitochondrial (Complex I-V) or apoptotic (BCL2/caspases). Multi-pathway convergent vulnerability: calcium/excitotoxicity (3/6), protein quality control (2/6), nitrosative stress (1/6)",
  "double_hit_model": {
    "description": "FOS (activity-dependent TF, SST_PLTS master regulator) directly regulates NOS1 (strongest neurodegeneration gene, padj=5.4e-72). Activity burden amplifies nitrosative stress vulnerability.",
    "tf": "FOS",
    "target": "NOS1",
    "implication": "During high-activity states (e.g. tic suppression), FOS activation \u2192 NOS1 upregulation \u2192 excess NO \u2192 mitochondrial Complex I inhibition + protein S-nitrosylation. Combined with calcium overload (CALM2/CHRM3/GRIA3) and stressed proteostasis (UCHL1/PRNP), creates convergent vulnerability."
  }
}