| Summary: | Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no defined molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43; and we propose a disease mechanism in which loss of function of one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms.
In support of this hypothesis, we found that depletion of FUS and TDP43 leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. This indicates that these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, we observed that both FUS and TDP43 co-localize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein BRCA1, and that FUS and TDP43 participate in the prevention or repair of R-loop associated DNA damage.
Ideally, gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage will shed light on the mechanisms underlying ALS pathogenesis.
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