Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown molecular causes.
• Proteins like FUS and TDP43, involved in RNA processing, are implicated in ALS pathogenesis.
• A potential mechanism involves DNA damage accumulation due to impaired RNA processing.

Purpose of the Study:

• To investigate the role of FUS and TDP43 in preventing transcription-associated DNA damage.
• To explore the link between FUS/TDP43 dysfunction, DNA damage, and ALS pathogenesis.
• To understand how these proteins contribute to motor neuron cell death in ALS.

Main Methods:

• Depletion of FUS or TDP43 in cellular models.
• Assessment of sensitivity to transcription-arresting agents.
• Analysis of DNA damage levels.
• Immunofluorescence to detect protein colocalization with RNA polymerase II and BRCA1 at DNA damage sites.

Main Results:

• FUS or TDP43 depletion increased sensitivity to DNA damage agents.
• These proteins normally protect against transcription-associated DNA damage.
• FUS and TDP43 colocalize with RNA polymerase II and BRCA1 at DNA damage sites.
• FUS and TDP43 are involved in repairing R-loop associated DNA damage.

Conclusions:

• FUS and TDP43 play a critical role in preventing or repairing transcription-associated DNA damage.
• Loss of FUS/TDP43 function may lead to DNA damage accumulation, contributing to motor neuron death in ALS.
• Understanding this pathway could reveal new therapeutic targets for ALS.