TDP-43 Proteinopathies

name: TDP-43 Proteinopathies
display_name: TDP-43 Proteinopathies
creation_date: "2026-06-18T00:00:00Z"
description: >-
  TDP-43 proteinopathies are neurodegenerative disorders whose mechanism graphs
  include pathological redistribution of TDP-43 from the nucleus to the
  cytoplasm, cytoplasmic TDP-43 aggregation, and/or nuclear loss of TDP-43
  RNA-processing function. The current DisMech grouping spans motor-neuron,
  parkinsonism-dementia, and repetitive-head-trauma-associated entries that
  declare conformance to the tdp43_proteinopathy module.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on the shared TDP-43 proteinopathy mechanism: members conform to the
  tdp43_proteinopathy module, with cytoplasmic TDP-43 aggregation and, when
  modeled, nuclear RNA-processing loss acting as a convergent neurodegenerative
  lesion. The members are kept distinct because their upstream triggers and
  clinical-anatomic presentations differ: ALS is a motor-neuron degeneration
  syndrome with genetic and sporadic subtypes, ALS-PDC is a Western Pacific
  parkinsonism-dementia-motor neuron complex, and CTE is associated with
  repetitive head impacts and includes TDP-43 pathology in a subset of cases.
membership_criteria:
- description: >-
    A disorder belongs to this grouping if and only if it conforms to the
    TDP-43 proteinopathy module, capturing cytoplasmic TDP-43 aggregation and/or
    nuclear loss of TDP-43 RNA-processing function as a disease mechanism.
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: tdp43_proteinopathy
    description: >-
      Conforms to the TDP-43 proteinopathy module.
members:
- member: Amyotrophic Lateral Sclerosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALS places TDP-43 pathology in vulnerable upper and lower motor neurons,
      with TARDBP, C9orf72, SOD1-negative/FUS-negative sporadic biology, and
      downstream STMN2/UNC13A RNA-processing defects contributing to the motor
      neuron degeneration phenotype.
    gene:
      preferred_term: TARDBP
      term:
        id: hgnc:11571
        label: TARDBP
- member: Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Complex
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ALS-PDC combines motor neuron disease, parkinsonism, and dementia in a
      long-latency Western Pacific neurodegenerative syndrome, with TDP-43
      aggregation modeled alongside environmental and excitotoxic contributors.
    biological_processes:
    - preferred_term: inclusion body assembly
      term:
        id: GO:0070841
        label: inclusion body assembly
      modifier: INCREASED
- member: Chronic Traumatic Encephalopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CTE is distinguished by repetitive-head-impact exposure and a primary
      tauopathy context; it enters this grouping because the curated mechanism
      includes cytoplasmic TDP-43 aggregation as a co-pathology in a subset of
      disease.
    biological_processes:
    - preferred_term: inclusion body assembly
      term:
        id: GO:0070841
        label: inclusion body assembly
      modifier: INCREASED
notes: >-
  This grouping intentionally avoids also adding a separate glutamate
  excitotoxicity grouping in the same change, because the current DisMech ALS
  entries would overlap heavily across both groupings.