TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons

TAR DNA-binding protein 43 (TDP-43) is a key player in neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Accumulation of TDP-43 is associated with neuronal death in the brain. How increased and disease-causing mutant forms of TDP-43 induce cell death remains unclear. Here we addressed the role of TDP-43 during neural development and show that reduced TDP-43 causes defects in neural stem/progenitor cell proliferation but not cell death. However, overexpression of wild type and TDP-43A315T proteins induce p53-dependent apoptosis of neural stem/progenitors and human induced pluripotent cell (iPS)-derived immature cortical neurons. We show that TDP-43 induces expression of the proapoptotic BH3-only genes Bbc3 and Bax, and that p53 inhibition rescues TDP-43 induced cell death of embryonic mouse, and human cortical neurons, including those derived from TDP-43G298S ALS patient iPS cells. Hence, an increase in wild type and mutant TDP-43 induces p53-dependent cell death in neural progenitors developing neurons and this can be rescued. These findings may have important implications for accumulated or mutant TDP-43 induced neurodegenerative diseases

Systematic review on noninvasive assessment of subclinical cardiovascular disease in obstructive sleep apnea: New kid on the block!

Patients with obstructive sleep apnea (OSA) have a high burden of cardiovascular disease (CVD) but a causal relationship between OSA and atherosclerotic CVD remains unclear. We systematically reviewed the literature analyzing the relationship. A review of the Medline database for studies noninvasively evaluating subclinical CVD in OSA was conducted. A total of fifty-two studies were included in this review.Across the studies the prevalence of atherosclerosis, as assessed by coronary artery calcification, carotid intima-media thickness, brachial artery flow-mediated dilation and pulse wave velocity was higher in patients with OSA and correlated with increasing severity and duration of OSA.This study shows OSA is an independent predictor of subclinical CVD as CVD is more likely to occur in patients with long standing and severe OSA. Further research is however necessary to identify specific OSA populations that would benefit from aggressive screening