RNA binding protein TDP-43 is found in ubiquitinated inclusions in a number of neurodegenerative diseases, most prominently Amyotrophic Lateral Sclerosis (ALS) and some forms of Frontotemporal Lobar Dementia (FTLD). Importantly, mutations in TDP-43, have been shown to be causal in the development of ALS. TDP-43 is a mostly nuclear protein with numerous characterized roles in RNA metabolism including the modulation of transcription, splicing and translation. However, the mechanism by which TDP-43 meditates neurotoxicity is unclear. C. elegans expresses a single TDP-43 homolog, TDP-1, which can substitute for TDP-43 in mammalian alternative splicing assays. Recent immunoprecipitation experiments with anti-TDP-43 antibodies followed by Mass-Spectrometry have identified the enzyme adenosine deaminase acting on RNA (ADAR) as a binding partner of TDP-43. ADAR enzymes are known to have pivotal roles in the nervous system, and it has been shown that motor neurons degenerating in ALS fail to appropriately edit the mRNA coding for GluR2, a glutamate receptor subunit. We are therefore investigating a role for TDP-1 in adenosine-to-inosine RNA editing. We find that deletion of
tdp-1 results in the mis-regulation of A to I RNA editing in published ADAR targets. Further, we find that deletion of
tdp-1 results in somatic sensitivity and germline resistance to RNAi. The possible roles of the C. elegans ADARs,
adr-1 and
adr-2, in these RNAi effects are currently being investigated. Preliminary data indicates that deletion of
tdp-1 and
adr-1 results in synthetic neuronal deficits, suggesting that TDP-1 modulation of RNA editing does have biological consequences.