Review
TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies

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Given the critical role for TDP-43 in diverse neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), there has been a recent surge in efforts to understand the normal functions of TDP-43 and the molecular basis of dysregulation that occurs in TDP-43 proteinopathies. Here, we highlight recent findings examining TDP-43 molecular functions with particular emphasis on stress-mediated regulation of TDP-43 localization, putative downstream TDP-43 target genes and RNAs, as well as TDP-43 interacting proteins, all of which represent viable points of therapeutic intervention for ALS, FTLD-TDP and related proteinopathies. Finally, we review current mouse models of TDP-43 and discuss their similarities and potential relevance to human TDP-43 proteinopathies including ALS and FTLD-TDP.

Section snippets

TDP-43 and neurodegeneration

Trans-activation response DNA-binding protein of 43 kDa (TDP-43), encoded by the TARDBP gene on chromosome 1, is a major component of tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS; see Glossary) and frontotemporal lobar degeneration (FTLD) linked to TDP-43 pathology (FTLD-TDP) [1]. TDP-43 aggregation and neuropathology have been observed in a spectrum of distinct neurodegenerative disorders collectively known as the TDP-43 proteinopathies,

TDP-43 regulates mRNA expression and gene transcription

TDP-43 is abundantly expressed in nearly all tissues and is well conserved among mammals and invertebrates [6]. Structural analysis has identified two RNA recognition motifs (RRMs) termed RRM1 and RRM2 that are capable of binding nucleic acids [7], and a glycine-rich region harboring the majority of ALS-associated mutations (Figure 1). TDP-43 binds both mRNA and DNA, thereby regulating mRNA splicing, stability and translation as well as gene transcription. Although early in vitro studies showed

TDP-43, stress granules and pathological aggregates

Although TDP-43 regulates mRNA levels under normal physiological conditions, accumulating evidence indicates that TDP-43 is a stress-responsive RNA-associated factor. Exposure to a variety of stressors including zinc [40] or the lipid mediator 15d-PGJ(2) [41], both of which promote oxidative stress, led to accumulation of insoluble TDP-43 aggregates similar to those observed under pathological conditions [1]. However, any definitive role for TDP-43 in initiating or executing an oxidative stress

Physiological and pathological TDP-43 interacting proteins

The identification of TDP-43 interacting proteins could provide crucial insight into the functions described above for TDP-43 in gene transcription, RNA binding and SG formation. Buratti et al. showed that the C-terminal region of TDP-43 is capable of binding directly to several proteins of the heterogeneous nuclear ribonucleoprotein (hnRNP) family including hnRNP A1/A2/B1 [59]. Recent proteomics analyses verified and extended these TDP-43 interactions to include several hnRNP family members

Mouse models of TDP-43 proteinopathies

TDP-43 protein levels are abundantly and widely expressed in most human tissues, including cells that comprise CNS tissues such as neurons and glia. Genetic and biochemical studies suggest that the abnormal sequestration of TDP-43 within neuronal and glial inclusions observed in diseased brains could reflect loss of TDP-43 functions resulting in disease onset or progression. To address the physiological role for TDP-43, several laboratories have generated Tardbp null mice and in all instances

Concluding remarks

Biochemical, neuropathological and genetic studies have shown that TDP-43 is a major component of ubiquitinated inclusions in ALS and FTLD-TDP and has sparked intense efforts to elucidate the role of RNA-binding proteins in neurodegenerative diseases [81]. Although it is emerging that TDP-43 nuclear functions, including gene transcription and mRNA regulation, are crucial for cell survival, the exact mechanisms by which TDP-43 regulates these processes remains uncertain. A detailed understanding

Glossary

Amyotrophic lateral sclerosis (ALS)
characterized by progressive degeneration of motor neurons.
Dinucleotide repeat element
repetitive nucleic acid sequences consisting of two nucleotides present in DNA or RNA that provide specificity for protein binding.
Eosinophilic
cytoplasmic structures staining positive with the acidic dye eosin, which can be used to characterize cytoplasmic protein aggregates in ALS and other neurodegenerative diseases.
FTLD-FUS (frontotemporal lobar degeneration linked to FUS

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