No abstract

Recently, mutations in the RNA polymerase III subunit 3A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A have important roles in the regulation of transcription of small RNAs, including tRNA, 5S rRNA and U6 snRNA. We aim to describe cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control were grown. Mutation in POLR3A causes a decreased in the expression of POLR3A mRNA and protein and a sharp increased of mutant protein.In addition, there was an increased in its nuclear localization. These changes were associated to an increase number and area of nucleoli, a significantly larger nuclear area, and a high increased in the expression of pP53 and pH2AX. All these changes were associated to premature senescence. The present observations add to our understanding of the differences between HGPS and WRS, and opens new alternatives to study cell senesce and human aging.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aβ) accumulation and neurofibrillary tangles formation in the brain which are associated to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathologic and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-β (Aβ) accumulation in the brain. However, the role of LXR with regard to the regulation of synaptic function remains relatively understudied. In the present paper, we analyzed the in-vitro effect of the LXR agonist GW3965 on synaptic function upon exposure of primary hippocampal cultures to oligomeric amyloid-β (oAβ(1-42)). We showed that oAβ(1-42) exposure significantly decreased the density of mature (mushroom shaped) dendritic spines density and synaptic contacts number. oAβ(1-42) also modulates the expression of pre- (VGlut1, SYT1, SV2A) and post-synaptic (SHANK2, NMDA) proteins, it decreases the expression of PINK1, and increases ROCKII, and activates of caspase-3; these changes were prevented by the pre-treating neuronal cultures with GW3965. These results show further support the role of the LXR agonist GW3965 in synaptic physiology and highlight its potential as an alternative pharmacological strategy for AD.