Molecular mechanisms of neuropathogenesis associated with the defects of DNA repair system

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Recent studies have shown that the defect of DNA repair/damage response mechanism in the nervous system closely associate with pathology underlying various neurodegenerative diseases. Accumulating results suggest that DNA damage may reduce transcriptional expression of genes involved in learning, memory and neuronal survival to initiate a program of brain ageing and pathogenesis. In this study, we focused on the molecular basis of DNA repair and damage responses underlying neurodegenerative diseases.We performed a proteome analysis of soluble nuclear proteins prepared from neurons expressing mutant huntingtin exon 1 fragment protein which contains abnormally expanded poly-glutamine repeat (mHtt), and found that mHtt reduces the concentration of nuclear HMGB1 protein level. We also found that the reduction of nuclear HMGB1 causes DNA double-strand break (DDSB)-mediated neuronal damage in Huntinton's disease pathology. Using gene transgenic animals of mouse and fly that overexpressing DNA repair/damage response genes, we found that the improvement of DNA repair significantly recovers the symptoms of Huntinton's disease pathology. Furthermore, we investigated the regional and cell-type specific changes of HMGB1 and DDSB accumulation during the aging of mouse brain. HMGB1 is localized in the nuclei of neurons and astrocytes, and the protein level changes in various brain regions age-dependently. HMGB1 reduces in neurons, whereas it increases in astrocytes during aging. In contrast, DDSB remarkably accumulates in neurons, but it does not change significantly in astrocytes during aging. These results indicate that HMGB1 expression is differentially regulated between neuron and astrocyte, and suggest that the reduction of nuclear HMGB1 might be associated with DDSB-mediated neuronal dysfunction in the aging brain.Our findings might provide us an effective strategy for developing new therapeutics against various neurodegenerative disorders.