This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (for example, "tdp43_proteinopathy#Cytoplasmic TDP-43 Aggregation"). The module is intended for the disorders unified by TDP-43 pathology: amyotrophic lateral sclerosis (TDP-43 positive in ~97% of cases), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP, including GRN- and C9orf72-associated forms), semantic dementia, inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD), chronic traumatic encephalopathy (where a TDP-43 proteinopathy occurs in a subset of cases), and limbic-predominant age-related TDP-43 encephalopathy (LATE) / TDP-43 co-pathology in Alzheimer disease. It is intentionally distinct from the polyglutamine_expansion_proteotoxicity module (translated polyQ tracts) and from tauopathy or alpha-synucleinopathy mechanisms: the unifying lesion here is the nuclear-to-cytoplasmic redistribution and aggregation of TDP-43 itself. SOD1- and FUS-associated ALS are explicit exceptions — they are TDP-43-negative and are out of scope for conformance to this module. Whether the principal toxic driver is nuclear loss of TDP-43 RNA-processing function or cytoplasmic gain-of-function aggregation remains debated and is captured across the aggregation and RNA-processing nodes.
TDP-43 Nuclear Clearance and Cytoplasmic Mislocalization
trigger
The shared initiating lesion is the redistribution of TDP-43 out of the neuronal nucleus, where it normally performs RNA-binding and splicing functions, into the cytoplasm. Diverse upstream triggers — TARDBP, GRN, or C9orf72 mutations, nuclear-pore-complex dysfunction, ageing, and repetitive head trauma — converge on this nuclear depletion and cytoplasmic accumulation, which is recoverable specifically from affected CNS regions and bridges sporadic and familial disease.
Downstream
-
Cytoplasmic TDP-43 Aggregation
Cytoplasmic TDP-43 self-associates into phosphorylated, ubiquitinated inclusions.
-
Nuclear Loss of TDP-43 RNA-Processing Function
Depletion of nuclear TDP-43 removes repression of cryptic exons and corrupts splicing of disease-relevant transcripts.
Cytoplasmic TDP-43 Aggregation
central effector
Mislocalized cytoplasmic TDP-43 is post-translationally modified (hyper-phosphorylated, ubiquitinated, C-terminally cleaved) and self-associates into insoluble inclusions, the defining histopathological hallmark of the TDP-43 proteinopathies. These aggregates burden proteostasis and represent the cytoplasmic gain-of-function arm of the coupled lesion. Whether the principal toxic species is a soluble mislocalized conformer or a mature inclusion remains debated, and visible inclusions may mark a late stage of a longer toxic cascade.
Downstream
-
Selective Neuronal Dysfunction and Loss
Cytoplasmic aggregation and proteostatic burden contribute to degeneration of vulnerable neuronal populations.
Nuclear Loss of TDP-43 RNA-Processing Function
amplifier
Depletion of nuclear TDP-43 removes its repression of nonconserved cryptic exons and corrupts splicing and polyadenylation of disease-relevant transcripts. Cryptic-exon inclusion in STMN2 lowers stathmin-2 (impairing axonal outgrowth and regeneration), and a cryptic exon in UNC13A — linked to common ALS/FTD risk variants — reduces UNC13A protein. This nuclear loss-of-function arm is the most concrete RNA-processing defect modeled as a causal bridge from TDP-43 redistribution toward neuronal death.
Downstream
-
Selective Neuronal Dysfunction and Loss
Transcript-specific RNA-processing failures (STMN2, UNC13A, and others) compromise axonal maintenance and synaptic function in vulnerable neurons.
Selective Neuronal Dysfunction and Loss
effector
The convergent effects of cytoplasmic aggregation (proteostatic gain-of-function) and nuclear RNA-processing failure (loss-of-function) produce the defining outcome of the TDP-43 proteinopathies: region- and cell-type-specific neuronal dysfunction and death despite ubiquitous TDP-43 expression. Each disorder targets a characteristic population — spinal and cortical motor neurons in ALS, frontotemporal cortical neurons in FTLD-TDP and semantic dementia, and limbic/cortical neurons in CTE and LATE — yielding the corresponding motor, behavioral, and cognitive phenotypes.