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
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Cytoplasmic TDP-43 Aggregation
Cytoplasmic TDP-43 self-associates into phosphorylated, ubiquitinated inclusions.
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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.
Show evidence (3 references)
"we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord."
The seminal Neumann et al. study establishes the conserved core of the module: pathological TDP-43 is the common disease protein across both frontotemporal lobar degeneration and ALS, present as hyper-phosphorylated, ubiquitinated cytoplasmic species in affected CNS regions.
"TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders."
Directly supports treating TDP-43 redistribution as a conserved cross-disease mechanism rather than an ALS-specific finding.
"TDP-43 bridges the divide between sporadic and familial ALS and remains a dominant protein of interest to understand disease pathogenesis."
Confirms that TDP-43 pathology unifies sporadic and familial disease, consistent with a convergent mechanism module driven by multiple upstream triggers.
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
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Selective Neuronal Dysfunction and Loss
Cytoplasmic aggregation and proteostatic burden contribute to degeneration of vulnerable neuronal populations.
Show evidence (2 references)
"TDP-43 was identified as a primary component of ubiquitinated and hyper-phosphorylated cytosolic aggregates observed from post-mortem tissue of patients with ALS"
Human postmortem evidence identifies cytoplasmic ubiquitinated, hyper-phosphorylated TDP-43 aggregates as the central effector lesion.
"These changes often include cerebral atrophy, cavum septi pellucidi with fenestrations, shrinkage of the mammillary bodies, dense tau immunoreactive inclusions (neurofibrillary tangles, glial tangles, and neuropil neurites), and, in some cases, a TDP-43 proteinopathy."
Extends the aggregation lesion beyond ALS/FTLD to chronic traumatic encephalopathy, where a TDP-43 proteinopathy occurs in a subset of cases — supporting the module's conservation across an environmentally triggered (repetitive head trauma) disorder.
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
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Selective Neuronal Dysfunction and Loss
Transcript-specific RNA-processing failures (STMN2, UNC13A, and others) compromise axonal maintenance and synaptic function in vulnerable neurons.
Show evidence (4 references)
"When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay."
Establishes the basic cryptic-exon and nonsense-mediated-decay mechanism that follows loss of nuclear TDP-43.
"repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy."
Human ALS-FTD tissue places impaired cryptic-exon repression within the TDP-43 proteinopathy mechanism, generalizing the node across the ALS-FTD spectrum.
"Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression."
Connects nuclear TDP-43 loss to a specific disease-relevant RNA target (UNC13A) implicated by common ALS/FTD risk variants.
+ 1 more reference
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.
Show evidence (2 references)
"STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration."
Provides a functional motor-neuron consequence of the TDP-43 loss-of-function arm, linking RNA-processing failure to impaired axonal maintenance in the vulnerable cell type.
"parkinsonism, and, occasionally, motor neuron disease are seen in affected individuals."
Documents that TDP-43-associated CTE can present with motor neuron disease and parkinsonism, illustrating the cross-disorder phenotypic selectivity that this effector node represents.