SUMMARY Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. Here, we report that FUS, a RNA/DNA binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), plays a pivotal role in DNA damage response (DDR). We show that the function of FUS in DDR involves a direct interaction with histone deacetylase 1 (HDAC1), and that the recruitment of FUS to double stranded break (DSB) sites is important for proper DDR signaling. Remarkably, FUS proteins carrying familial ALS (fALS) mutations are defective in DDR and DNA repair, and show a diminished interaction with HDAC1. Moreover, increased DNA damage was also observed in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.

We identified a novel pathogenicity island inInterestingly, these strains are mainly isolated from other sources of infections and not from patients with bullous impetigo or staphylococcal scalded-skin syndrome. This strongly suggests that ETD might play a pathogenic role in a broader spectrum of bacterial infections than previously considered.

Background and Purpose-Few studies are available that have addressed the prevalence of early-onset dementia (EOD), including early-onset Alzheimer disease and other forms of dementia in Japan. Methods-A 2-step postal survey was sent to all of the 2475 institutions providing medical or care services for individuals with dementia in Japan's Ibaraki prefecture (population, 2 966 000) requesting information on EOD cases. Data were then reviewed and collated. Results-We identified 617 subjects with EOD. The estimated prevalence of EOD in the target population was 42.3 per 100 000 (95% CI, 39.4 to 45.4). Of the illnesses that cause EOD, vascular dementia was the most frequent (42.5%) followed by Alzheimer disease (25.6%), head trauma (7.1%), dementia with Lewy bodies/Parkinson disease with dementia (6.2%), frontotemporal lobar degeneration (2.6%), and other causes (16.0%). Conclusions-The prevalence of EOD in Japan appeared to be similar to that in Western countries with the notable exception that vascular dementia was the most frequent cause of EOD in Japan.