Tuesday, 27 November 2018 | 12:00 noon
Director of the Institute of Scientific Researchand Technological Advances – INDICASAT AIP, PANAMA
DNA dynamics in neuro degenerative disorders
(Host: M. Giacca)
DNA dynamics in terms of conformation and stability, proposes to play a key role in neuronal cell death in neurodegenerative disorders. Our studies showed DNA conformation changes from B-DNA to Z-DNA in Alzheimer’s disease, B to modified B in Parkinson Disease and further accumulation of strand breaks leading to DNA stability changes in cells. Recently we showed that proteins like synuclein causing the chromatin instability in Parkinson disease cell model. Now we propose a concept that loss of nuclear TDP-43 has been linked to amyotrophic lateral sclerosis (ALS), which also features increased genome damage in affected neurons.
However, its role in the DNA damage response (DDR) has not been investigated. Here, we report that TDP-43 is a critical component of the non- homologous end joining (NHEJ)-mediated DNA double- strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with NHEJ and DDR factors, specifically acting as a scaffold for XRCC4- DNA Ligase 4 complex in spinal motor neurons. Total or nucleus-specific knockdown of TDP-43 markedly increased genomic DSBs by impairing DSB ligation for NHEJ and sensitized cells to DSB stress. Finally, ALS-mimicking TDP-43 pathology strongly correlated with NHEJ defects, and DSB accumulation in the spinal cord of ALS patients, and C. elegans model. Our findings thus link TDP43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease.