limbic-predominant age-related TDP-43 encephalopathy
In 2006, TAR DNA-binding protein 43 (TDP-43) was identified as the cardinal protein in the most common subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Together with the 2006 discovery of progranulin, this was a major breakthrough in the study of FTD.
TDP-43 is a widely expressed nuclear protein that binds both DNA and RNA. While shuttling between nucleus and cytoplasm, it helps regulate many aspects of RNA processing, such as splicing, trafficking, stabilization, and miRNA production. For example, TDP-43 affects RNAs that encode proteins involved in autophagy and other cellular protein homeostasis and clearance pathways. A role in axonal transport has also been proposed. In neurodegenerative diseases, neuronal and glial TDP-43 becomes mislocalized to the cytoplasm, where it aggregates into stress granules and insoluble inclusion bodies. These inclusions occur in all people with FTD or ALS caused by mutations in C9ORF72, progranulin, valosin-containing protein, or TDP-43 itself, as well as in some familial cases of unknown mutation and some sporadic cases, and in about a quarter of Alzheimer’s disease cases.
Regardless of the proximal cause of a given patient’s disease, distribution of TDP-43 pathology tends to correlate with brain areas of atrophy and the stage of dementia, hence TDP-43 dysregulation is considered to reflect a common downstream mechanism of neurodegeneration. A staging scheme to classify TDP pathology at autopsy has been proposed. Whether the inclusions themselves or soluble species are toxic remains unclear.
TDP-43 protein is 96 percent identical between human and mice, and more than a dozen knockout and transgenic lines of wild-type and mutant TDP-43 have been created. Most reflect some pathologic features of ALS/FTD but not the corresponding functional deficits; brain-specific conditional models may be required. Zebrafish, fruit fly, worm, and human induced pluripotent stem cell models exist as well, and are used in efforts to define the protein’s role in the pathogenesis of these diseases.
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