TDP-43 immunoreactivity in neurodegenerative disorders: disease versus mechanism specificity

Excerpt

Recently, the TAR DNA binding protein 43 (TDP-43) has been shown to be present in neuronal inclusions in frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (FTLD-U), as well as in amyotrophic lateral sclerosis (ALS) [17]. TDP-43, a nuclear DNA binding protein that is involved in transcriptional regulation, is aberrantly deposited in filamentous cytoplasmic inclusions subsequent to a series of post-translational modifications including proteolysis, phosphorylation and ubiquitination [17]. Neuronal cytoplasmic inclusions have been known to be a consistent feature of motor neuron degeneration in ALS for over a decade [12, 14], but their molecular composition was not known. Prior to this discovery, the motor neuron inclusions of ALS were only known to be immunoreactive for ubiquitin [12, 14] and the ubiquitin-binding protein p62/sequestosome [15], but these markers are not disease specific and can be detected in inclusions in a wide range of other disorders as well as inclusions and other pathology in the normal aged brain. Consequently, it was difficult to determine what was disease specific in these cases, especially for inclusions that were present in extra-motor regions of the nervous system. This problem has apparently been resolved with the discovery of TDP-43, which has been suggested to be a specific marker for ALS. It is present in the neuronal (and glia) inclusions in all cases of ALS that have been studied, except for those that are found in the setting of familial ALS due to mutations in the superoxide dismutase-1 gene [13, 19]. At present it is unknown if TDP-43 will be present in inclusions in familial ALS due to mutations in other genes. …