TAR DNA-binding protein 43 in neurodegenerative disease

Abstract

In 2006, TAR DNA-binding protein 43 (TDP-43), a highly conserved nuclear protein, was identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and in the most common variant of frontotemporal lobar degeneration (FTLD), FTLD-U, which is characterized by cytoplasmic inclusions that stain positive for ubiquitin but negative for tau and alpha-synuclein. Since then, rapid advances have been made in our understanding of the physiological function of TDP-43 and the role of this protein in neurodegeneration. These advances link ALS and FTLD-U (now designated FTLD-TDP) to a shared mechanism of disease. In this Review, we summarize the current evidence regarding the normal function of TDP-43 and the TDP-43 pathology observed in FTLD-TDP, ALS, and other neurodegenerative diseases wherein TDP-43 pathology co-occurs with other disease-specific lesions (for example, with amyloid plaques and neurofibrillary tangles in Alzheimer disease). Moreover, we discuss the accumulating data that support our view that FTLD-TDP and ALS represent two ends of a spectrum of primary TDP-43 proteinopathies. Finally, we comment on the importance of recent advances in TDP-43-related research to neurological practice, including the new opportunities to develop better diagnostics and disease-modifying therapies for ALS, FTLD-TDP, and related disorders exhibiting TDP-43 pathology.

Figure 1

Physiological and pathophysiological TDP-43. a | Under physiological conditions, TDP-43 primarily resides in the nucleus, although the protein has the capacity to shuttle between the nucleus and the cytoplasm. TDP-43 has been reported to have roles in regulating gene expression at the transcriptional level, regulating gene splicing, and stabilizing mRNA. b | Under pathophysiological conditions, TDP-43 is cleared from the nuclear compartment and accumulates in the cytoplasm. Pathological TDP-43 has been demonstrated to be hyperphosphorylated and/or ubiquitinated. Furthermore, small carboxy-terminal fragments of TDP-43 can be found in the disease state. Pathological TDP-43 is also less soluble than TDP-43 under physiological conditions, possibly making the former more prone to aggregation. The changes that occur in the nature of TDP-43 under pathophysiological conditions might result in various loss-of-function or toxic-gain-of-function mechanisms of pathogenesis. Abbreviation: mRNA, messenger RNA; P, phosphate group; TDP-43, TAR DNA-binding protein 43; U, ubiquitin group.

Figure 2

Domain structure and disease-associated mutations of TDP-43. TDP-43 shares structural similarities with heterogeneous nuclear ribonucleoproteins, with a domain structure consisting of two RBDs followed by a glycine-rich domain. At least 32 different mutations (indicated by the single letter amino acid code) in TARDBP—the gene encoding TDP-43—have been reported to cause disease in humans. Most of these mutations occur within the glycine-rich domain. At least two of these mutations (Gly295Ser and Lys263Glu) might cause frontotemporal lobar degeneration, although the majority of TARDBP mutations have been reported in patients with amyotrophic lateral sclerosis. Abbreviations: NLS, nuclear localization signal; RBD, RNA binding domain; TDP-43, TAR DNA-binding protein 43.

Figure 3

TDP-43 histopathology. Immunohistochemistry with an anti-TDP-43 antibody reveals robust staining of ubiquitinated inclusions (brown staining). TDP-43 pathology in FTLD-TDP can be classified into four subtypes, three of which are shown here in frontal cortex tissue: a | type 1 pathology, b | type 2 pathology and c,d | type 3 pathology. e,f | Immunostaining showing TDP-43 inclusions (arrowheads) and nuclear clearance (arrows) in neurons in the hippocampal dentate gyrus. Other morphologies of TDP-43-immunoreactive histopathology include g | intranuclear inclusions, h | lentiform inclusions, and i | round inclusions in motor neurons of the spinal cord. Abbreviations; FTLD-TDP, frontotemporal lobar degeneration with TDP-43 inclusions; TDP-43, TAR DNA-binding protein 43. Reprinted with permission from AAAS © Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

Figure 4

TDP-43 in FTLD and ALS. Approximately 50% of cases of clinical FTLD exhibit TDP-43 pathology, with the remainder characterized by either tau pathology or other forms of neuropathology, notably FUS inclusions. TDP-43 pathology is observed in the vast majority of ALS cases. In addition, overlap syndromes between FTLD and ALS (for example, FTLD–MND) most frequently show TDP-43 pathology. A subset of individuals with FTLD-tau have mutations in MAPT, while some FTLD-TDP cases are associated with mutations in GRN. Mutations in TARDBP can be found in FTLD-TDP FTLD–MND and ALS, although the vast majority of these mutations manifest clinically as ALS. Abbreviations: ALS, amyotrophic lateral sclerosis; ALS-TDP, ALS with TDP-43-positive inclusions; FTLD, frontotemporal lobar degeneration; FTLD-FUS, FTLD with FUS-positive inclusions; FTLD–MND, FTLD with motor neuron disease; FTLD-tau, FTLD with tau-positive inclusions; FTLD-TDP FTLD with TDP-43-positive inclusions; TDP-43, TAR DNA-binding protein 43.