TDP43 (a nuclear DNA-RNA binding protein) is involved in splicing, RNA transport and stability in neurons. It was first identified as a pyrimidine rich TAR DNA sequence in HIV type 1 gene to modulate HIV gene expression. In 95% of the ALS patients, TDP43 is abnormal located within the cell and may also be aggregated, abnormally phosphorylated and accumulates in cytoplasmic inclusions while being depleted from the nucleus. Mutations in TDP43 does cause familial or even sporadic ALS with mutations in G348C and N352C mutions in a small german family. Interestingly, N352S may increase TDP43 phosphorylation and G348C may affect disulfide bridge formation. TDP43 is found is ALS but also in patients with frontotemporal dementia (FTD) and animal and cell models show that removal of aggregates enhances survival of neurons and reverse motor deficits in animal models.
Normally, TDP43 is present only in the nucleus but aggregates tend to be found in the cytoplasm. The abnormal TDP43 is unusually phosphorylated, ubiquitinated, or truncated. There are 2 types of effects – loss of function of normal TDP43 and gain of function of aggregated TDP43. But because these aggregates are considered toxic, there are many studies in progress which help in decreasing the aggregates. For example, Rapamycin, a mTOR inhibitor is though to enable autophagy of molecules is undergoing studies for ALS. VTx-002 from Vector Y is an AAV mediated gene therapy that binds pathological aggregates only received fast track designation for ALS. In that case the gene integrated into the genome will continue to express the antibody against the abnormal aggregates. There are many other studies in progress.
For diagnosing TDP43 mutations a study NCT05542576 is trying to see if they can detect TDP43 in retina of eyes using a retinal tracer called AMDX-2011P.
There are many other studies in progress to understand the role of TDP43.
