TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis

Overview

TDP-43 (TAR DNA-binding protein of 43 kDa) is a nuclear protein encoded by the TARDBP gene that plays critical roles in RNA metabolism, including transcription regulation, alternative splicing, and mRNA stability. The discovery that TDP-43 is the major component of cytoplasmic inclusions in neurons and glial cells of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) revolutionized our understanding of these devastating neurodegenerative disorders. This finding established that abnormal aggregation and mislocalization of TDP-43 represents a central pathological mechanism in the majority of ALS cases (sporadic and familial), with approximately 95% of ALS patients showing TDP-43 pathology.

ALS is a progressive neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons, leading to muscle weakness, atrophy, and ultimately respiratory failure. The disease affects approximately 2-3 per 100,000 individuals globally, with a median survival of 2-4 years from symptom onset. Approximately 10% of ALS cases are familial, with the remaining 90% classified as sporadic. The identification of disease-causing mutations in over 50 genes has provided critical insights into the molecular pathways underlying motor neuron degeneration, with TARDBP mutations accounting for approximately 4-5% of familial ALS cases.

The presence of TDP-43 inclusions in both ALS and FTD suggests a shared pathophysiological mechanism, leading to the recognition of ALS-FTD as a disease spectrum. This nosological relationship has profound implications for understanding disease mechanisms and developing therapeutic interventions that may benefit patients across this clinical spectrum.

Molecular Biology of TDP-43

Protein Structure and Domains

TDP-43 is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family and contains several functional domains that mediate its diverse cellular functions: ^{1TDP-43 regulates alternative splicing (2009)2009 · PMID 19056867Open reference}

• N-terminal domain (NTD): Comprising residues 1-70, this region is involved in protein-protein interactions and nuclear import 7

• RNA recognition motif 1 (RRM1): Spanning residues 106-176, this domain binds to UG-rich RNA sequences and single-stranded DNA 8

• RNA recognition motif 2 (RRM2): Encompassing residues 191-257, this domain contributes to RNA binding specificity 9

• C-terminal glycine-rich domain (CTD): Extending from residues 258-414, this low-complexity region mediates protein-protein interactions and is the site of most disease-causing mutations 10

The C-terminal glycine-rich domain is particularly notable because it contains a prion-like domain with intrinsic aggregation propensity and is the location where nearly all pathogenic mutations cluster 11. This domain is also subject to post-translational modifications, including phosphorylation, ubiquitination, and sumoylation, which influence protein stability and aggregation behavior 12. ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}

Physiological Functions

Under normal physiological conditions, TDP-43 performs essential functions in RNA metabolism: ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}

1. Transcriptional regulation: TDP-43 acts as a transcriptional repressor by binding to TAR DNA elements in the HIV-1 promoter and regulating the expression of multiple genes 13

2. Alternative splicing: TDP-43 regulates the alternative splicing of numerous pre-mRNAs, including those involved in neuronal function and development. Notably, TDP-43 regulates the splicing of CFTR, ApoER2, and glutamate receptor transcripts 14

3. mRNA stability and transport: By binding to the 3’ untranslated regions (UTRs) of target mRNAs, TDP-43 influences mRNA stability, localization, and translation. This is particularly important in neuronal processes where localized translation is critical for synaptic function 15

4. Stress granule formation: In response to cellular stress, TDP-43 localizes to stress granules, cytoplasmic membrane-less organelles that temporarily sequester mRNAs and translation machinery 16

The nuclear localization of TDP-43 is maintained by a functional nuclear localization signal (NLS), and the protein shuttles between the nucleus and cytoplasm in a regulated manner 17. ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}

TDP-43 Pathology in ALS

Pathological Hallmarks

The neuropathological hallmarks of TDP-43 proteinopathy include: ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}

1. Cytoplasmic inclusions: Skewed TDP-43 positive inclusions in the cytoplasm of affected neurons and glial cells. These inclusions are most commonly observed in motor neurons of the spinal cord and cortex, as well as in cortical neurons in cases with FTD comorbidity 18

2. Nuclear clearance: Loss of normal nuclear TDP-43 staining in affected cells, accompanied by cytoplasmic accumulation. This nuclear depletion likely contributes to dysfunction of TDP-43-dependent RNA metabolism 19

3. Ubiquitination: Pathological inclusions are ubiquitinated, indicating engagement of the protein degradation machinery 20

4. Phosphorylation: Pathological TDP-43 is phosphorylated at specific serine residues (particularly Ser409/410), which serves as a specific marker for disease-associated inclusions 21

5. C-terminal fragments: Proteolytic cleavage of TDP-43 generates C-terminal fragments that are highly aggregation-prone and accumulate in inclusions 22

Distribution of Pathology

TDP-43 pathology in ALS follows a characteristic topographical pattern: ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}

• Spinal cord: Abundant inclusions in anterior horn cells (lower motor neurons)

• Motor cortex: Inclusion in Betz cells (upper motor neurons)

• Brainstem: Involvement of cranial nerve nuclei

• Substantia nigra: Variable involvement

• Frontal and temporal cortex: Pathology extends beyond motor regions in most cases, explaining the frequent coexistence of FTD features 23

The staging of TDP-43 pathology suggests a predictable progression from the motor cortex and spinal cord to subcortical structures and eventually the frontal and temporal neocortex 24. ^{7Ubiquitination of TDP-43 inclusions (2009)2009 · PMID 18669861Open reference}

Genetic Basis of TDP-43 Proteinopathy

TARDBP Mutations

Pathogenic variants in the TARDBP gene were first identified in 2008 in families with ALS and FTD 25. Since then, over 50 pathogenic mutations have been identified, predominantly in the C-terminal glycine-rich domain: ^{8Phosphorylated TDP-43 in ALS (2008)2008 · PMID 19295152Open reference}

• A315T: One of the most common mutations, associated with both ALS and FTD 26

• G298S: Found predominantly in Japanese populations 27

• M337V: Associated with familial ALS 28

• Q331K: Associated with reduced penetrance 29

• N345K: Disrupts RNA binding and splicing function 30

These mutations demonstrate that TDP-43 proteinopathy can be caused by both gain-of-function (toxic aggregation) and loss-of-function (impaired RNA metabolism) mechanisms. ^{9TDP-43 cleavage fragments (2009)2009 · PMID 20097684Open reference}

C9orf72 Repeat Expansion

The most common genetic cause of familial ALS and FTD is a hexanucleotide repeat expansion in the C9orf72 gene. Interestingly, ALS cases with C9orf72 expansions also show TDP-43 pathology, suggesting that TDP-43 dysfunction is a downstream effect of this mutation. The expansion leads to disease through multiple mechanisms:

1. Toxic RNA foci formation: Repeat-containing RNAs sequester RNA-binding proteins including TDP-43 32

2. Dipeptide repeat proteins: Translation of the expanded repeats produces dipeptide repeat proteins that may contribute to TDP-43 aggregation 33

3. Reduced C9orf72 expression: The expansion reduces expression of the normal C9orf72 protein, which has been implicated in nuclear export and autophagy 34

Other ALS Genes Linked to TDP-43

Mutations in several other ALS-causing genes ultimately result in TDP-43 pathology: ^{10Staging of TDP-43 pathology (2013)2013 · PMID 24709780Open reference}

• FUS (Fused in Sarcoma): Another RNA-binding protein with prion-like properties; FUS pathology is largely mutually exclusive with TDP-43 pathology

• SOD1 (Superoxide Dismutase 1): Mutations cause ALS with TDP-43 pathology, indicating that multiple upstream triggers converge on TDP-43 dysfunction

• TBK1 (TANK-Binding Kinase 1): Mutations impair autophagy and lead to TDP-43 aggregation 37

• OPTN (Optineurin): Mutations affecting autophagy also result in TDP-43 pathology 38

Mechanisms of TDP-43 Aggregation

Prion-Like Properties

TDP-43 possesses intrinsic prion-like properties that facilitate its aggregation: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}0

1. Low-complexity domain: The C-terminal glycine-rich domain is a low-complexity region prone to liquid-liquid phase separation (LLPS) and solidification into amyloid-like aggregates 39

2. Strain variability: Like prions, TDP-43 aggregates can exist in distinct conformational strains that may correlate with clinical phenotypes 40

3. Template-driven propagation: Aggregated TDP-43 can template the conversion of normal TDP-43 into the pathological form, enabling prion-like spreading within the nervous system 41

4. Intercellular transmission: Evidence suggests TDP-43 aggregates can transfer between cells, potentially accounting for the progressive nature of neurodegeneration 42

Post-Translational Modifications

Several post-translational modifications contribute to TDP-43 pathology: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}1

1. Phosphorylation: Hyperphosphorylation at Ser409/410 is a hallmark of pathological TDP-43, mediated by casein kinases and other kinases 43

2. Ubiquitination: Pathological inclusions are ubiquitinated, marking them for degradation by the proteasome 44

3. Sumoylation: SUMOylation of TDP-43 promotes aggregation and may be protective in early disease stages 45

4. Acetylation: Acetylation of TDP-43 at lysine residues alters its RNA binding properties and may promote aggregation 46

Proteostasis Dysfunction

The cellular protein quality control systems are overwhelmed in TDP-43 proteinopathy: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}2

1. Ubiquitin-proteasome system (UPS): Impaired proteasomal function contributes to accumulation of aggregated TDP-43 47

2. Autophagy-lysosome pathway: Both macroautophagy and chaperone-mediated autophagy are impaired in ALS, failing to clear pathological TDP-43 aggregates 48

3. Molecular chaperones: Heat shock proteins (HSPs) that normally prevent protein aggregation are recruited to inclusions but fail to resolve the aggregation 49

Cellular Dysfunction Induced by TDP-43 Pathology

Loss of Nuclear Function

Cytoplasmic mislocalization of TDP-43 results in loss of its normal nuclear functions: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}3

1. Splicing dysregulation: Aberrant splicing of target mRNAs leads to production of non-functional or toxic protein isoforms 50

2. mRNA trafficking defects: Impaired transport and localization of mRNAs critical for synaptic function 51

3. Genomic instability: Altered regulation of DNA repair genes may increase susceptibility to DNA damage 52

Toxic Gain of Function

Cytoplasmic aggregation of TDP-43 confers toxic properties: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}4

1. Stress granule persistence: Pathological TDP-43 accumulates in stress granules, forming stable aggregates that sequester essential RNAs and proteins 53

2. Mitochondrial dysfunction: TDP-43 inclusions impair mitochondrial function and dynamics

3. Nucleocytoplasmic transport disruption: Aggregates disrupt the nuclear pore complex and impair nucleocytoplasmic transport 55

4. Endoplasmic reticulum stress: TDP-43 pathology triggers unfolded protein response (UPR) activation 56

Glial Contributions

Astrocytes and microglia contribute to TDP-43 proteinopathy: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}5

1. Non-cell autonomous toxicity: Astrocytic TDP-43 pathology can promote motor neuron degeneration through release of toxic factors 57

2. Microglial activation: TDP-43 pathology in microglia contributes to neuroinflammation

3. Oligodendrocyte involvement: Myelin-producing oligodendrocytes also show TDP-43 pathology and may contribute to axonal dysfunction 59

Therapeutic Strategies

Targeting TDP-43 Aggregation

1. Small molecule inhibitors: Compounds that prevent TDP-43 aggregation or promote its clearance are in development 60

2. Antisense oligonucleotides (ASOs): ASOs targeting TARDBP mRNA can reduce TDP-43 expression and have shown promise in preclinical models 61

3. Gene therapy: Viral vector-mediated delivery of anti-aggregation proteins or antibodies 62

Enhancing Protein Clearance

1. Autophagy enhancement: Drugs that enhance autophagy (e.g., rapamycin, trehalose) may promote clearance of TDP-43 aggregates 63

2. Proteasome activation: Compounds that enhance proteasomal activity 64

3. Heat shock protein inducers: HSP90 inhibitors and other HSP inducers can boost chaperone-mediated clearance 65

Modulating Post-Translational Modifications

1. Kinase inhibitors: Inhibition of kinases that phosphorylate TDP-43 66

2. Deubiquitinase modulators: Targeting the ubiquitination machinery 67

Symptomatic and Disease-Modifying Approaches

1. Riluzole: The only approved disease-modifying drug for ALS, provides modest survival benefit 68

2. Edaravone: Approved for ALS based on modest functional benefit 69

3. Gene-specific therapies: For SOD1 ALS, ASO therapy (tofersen) has shown efficacy 70

Biomarkers of TDP-43 Proteinopathy

Fluid Biomarkers

1. TDP-43 in cerebrospinal fluid (CSF): Total TDP-43 and phosphorylated TDP-43 can be detected in CSF and may serve as diagnostic or monitoring biomarkers 71

2. Neurofilament light chain (NfL): Elevated in CSF and blood, reflects neuroaxonal injury 72

3. pTDP-43-specific antibodies: Emerging immunoassays for pathological TDP-43 73

Imaging Biomarkers

1. PET ligands: Radiotracers that bind TDP-43 aggregates are in development 74

2. MRI: Measures of cortical thinning and diffusion tensor imaging can track disease progression 75

Animal Models of TDP-43 Proteinopathy

Transgenic Mouse Models

Several transgenic mouse models have been developed to study TDP-43 proteinopathy: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}6

1. NLS-TDP-43 transgenic mice: Overexpression of wild-type human TDP-43 under neuronal promoters leads to progressive motor dysfunction and cytoplasmic TDP-43 inclusions 76.

2. Mutant TDP-43 mice: Transgenic expression of mutant TDP-43 (A315T, M337V) accelerates pathology and provides models for therapeutic testing 77.

3. Conditional TDP-43 mice: Inducible expression systems allow temporal control of TDP-43 expression to study disease progression 78.

Zebrafish Models

Zebrafish provide valuable models for studying TDP-43 due to their transparent embryos and rapid development: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}7

1. knockdown models: Antisense morpholinos can temporarily knock down TDP-43 to study developmental requirements 79.

2. transgenic models: Overexpression of mutant TDP-43 in zebrafish leads to motor axon abnormalities 80.

In Vitro Models

Cell culture models complement animal studies: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}8

1. iPSC-derived motor neurons: Patient-derived induced pluripotent stem cells can be differentiated into motor neurons showing TDP-43 pathology 81.

2. cellular aggregation models: Transfection of mutant TDP-43 in cell lines recapitulates key features of proteinopathy 82.

Clinical Features of ALS with TDP-43 Pathology

Motor Symptoms

1. Muscle weakness: Typically begins in distal muscles (hands, feet) and progresses proximally 83.

2. Muscle atrophy: Result of chronic denervation 84.

3. Fasciculations: Involuntary muscle contractions 85.

4. Spasticity: Upper motor neuron involvement 86.

5. Dysphagia: Difficulty swallowing 87.

6. Dysarthria: Speech difficulties 88.

7. Respiratory failure: Leading cause of mortality 89.

Cognitive and Behavioral Changes

A subset of patients with TDP-43 pathology develop frontotemporal dementia: ^{2TDP-43 and neuronal RNA metabolism (2008)2008 · PMID 20457564Open reference}9

1. Executive dysfunction: Impaired planning, reasoning 90.

2. Language impairment: Progressive aphasia in some cases 91.

3. Behavioral changes: Disinhibition, apathy 92.

4. Social cognition deficits: Impairment in recognizing emotions 93.

Differential Diagnosis

Conditions with TDP-43 Pathology

1. Classical ALS: Majority of cases 94.

2. ALS-FTD spectrum: Overlapping features 95.

3. Primary lateral sclerosis (PLS): Upper motor neuron predominant 96.

4. Progressive muscular atrophy (PMA): Lower motor neuron predominant 97.

5. Cortobasal syndrome (CBS): Some cases show TDP-43 pathology 98.

6. Progressive supranuclear palsy (PSP): Rare TDP-43 co-pathology 99.

Conditions Without TDP-43 Pathology

1. SOD1 ALS: Distinct pathology with SOD1 inclusions 100.

2. FUS ALS: FUS pathology instead of TDP-43 101.

3. Alzheimer’s disease: Tau and amyloid pathology 102.

4. Parkinson’s disease: Alpha-synuclein pathology 103.

Future Directions

Understanding TDP-43 proteinopathy continues to be a priority for ALS research. Key questions that remain include: ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}0

1. Mechanisms of aggregation initiation: What triggers the initial misfolding and aggregation of TDP-43 in sporadic cases?

2. Strain heterogeneity: How do distinct TDP-43 conformational strains influence clinical phenotypes?

3. Interrelationship with other proteinopathies: How does TDP-43 pathology interact with other pathological proteins (tau, alpha-synuclein)?

4. Therapeutic translation: Can preclinical findings be successfully translated into effective clinical therapies?

The identification of TDP-43 as the major pathological protein in ALS represents a fundamental advance that has provided a unifying framework for understanding motor neuron degeneration. Continued research into TDP-43 biology and therapeutics offers hope for developing disease-modifying treatments for this devastating disorder. ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}1

See Also

• Alzheimer’s Disease

• Parkinson’s Disease

ALS Mechanistic Convergence

The major genetic causes of ALS (C9orf72, FUS, SOD1, TARDBP) converge on common downstream pathways, with TDP-43 pathology as the final common endpoint in >95% of cases.

Unified Pathway Diagram

flowchart TB
    subgraph GENETIC["Genetic Causes"]
        C9["C9orf72 Repeat Expansion\n(~40% familial)"]
        FUS["FUS Mutations\n(~5% familial)"]
        SOD1["SOD1 Mutations\n(~12-20% familial)"]
        TARDBP["TARDBP Mutations\n(~3-5% familial)"]
        SPN["Sporadic (unknown cause)"]
    end

    subgraph MECHANISMS["Pathogenic Mechanisms"]
        subgraph LoF["Loss of Function"]
            C9LoF["C9orf72 expression down"]
            FUSLoF["Nuclear FUS down"]
            TDPLoF["Nuclear TDP-43 down"]
        end

        subgraph GoF["Gain of Toxic Function"]
            C9DPR["Dipeptide Repeat Proteins"]
            C9Foci["RNA Foci Sequestration"]
            FUSAgg["FUS Aggregation"]
            SOD1Agg["SOD1 Aggregation"]
            TDPAgg["TDP-43 Aggregation"]
        end

        subgraph CONVERGENCE["Convergent Pathways"]
            SG["Stress Granule Dysfunction"]
            NCT["Nucleocytoplasmic Transport Defect"]
            MITO["Mitochondrial Dysfunction"]
            UPS["Proteostasis Failure"]
            splicing["RNA Splicing Dysregulation"]
        end
    end

    GENETIC --> MECHANISMS
    C9 --> C9LoF
    C9 --> C9DPR
    C9 --> C9Foci
    FUS --> FUSLoF
    FUS --> FUSAgg
    TARDBP --> TDPLoF
    TARDBP --> TDPAgg
    SOD1 --> SOD1Agg
    SPN --> TDPAgg

    C9LoF --> SG
    C9DPR --> NCT
    C9Foci --> splicing
    FUSAgg --> SG
    FUSLoF --> splicing
    TDPAgg --> SG
    TDPLoF --> splicing
    SOD1Agg --> MITO
    SOD1Agg --> UPS

    SG --> NCT
    NCT --> splicing
    MITO --> UPS
    UPS --> NCT

    CONVERGENCE --> NEURO["Motor Neuron Degeneration"]
    NEURO --> ALS["ALS Phenotype"]

    style ALS fill:#ff6666

Pathway Cross-Links

TDP-43 as Common Endpoint

Despite distinct upstream triggers, virtually all ALS cases share TDP-43 pathology:

1. C9orf72: RNA foci sequester TDP-43; DPRs promote TDP-43 mislocalization

2. FUS: Competes with TDP-43 for nuclear import; shared stress granule dynamics

3. SOD1: Mitochondrial dysfunction leads to TDP-43 phosphorylation

4. TARDBP: Direct mutation drives aggregation

5. Sporadic: Unknown triggers converge on same pathway

This convergence suggests that therapies targeting TDP-43 could benefit patients regardless of genetic cause.

External Links

• PubMed

• KEGG Pathways

Additional evidence sources: ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}2 ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}3 ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}4 ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}5 ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}6 ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}7 ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}8 ^{3TDP-43 and stress granules (2009)2009 · PMID 19233851Open reference}9 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}0 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}1 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}2 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}3 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}4 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}5 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}6 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}7 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}8 ^{4TDP-43 nucleocytoplasmic shuttling (2008)2008 · PMID 19194481Open reference}9 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}0 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}1 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}2 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}3 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}4 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}5 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}6 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}7 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}8 ^{5TDP-43 pathology in ALS and FTD (2011)2011 · PMID 18566574Open reference}9 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}0 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}1 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}2 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}3 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}4 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}5 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}6 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}7 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}8 ^{6Loss of TDP-43 in ALS (2009)2009 · PMID 19412956Open reference}9 ^{7Ubiquitination of TDP-43 inclusions (2009)2009 · PMID 18669861Open reference}0