Presenilins as Drug Targets for Alzheimer's Disease-Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development.

A major cause underlying familial Alzheimer's disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aß). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aß. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.

p53-inducible long non-coding RNA PICART1 mediates cancer cell proliferation and migration.

Long non-coding RNAs (lncRNAs) function in the development and progression of cancer, but only a small portion of lncRNAs have been characterized to date. A novel lncRNA transcript, 2.53 kb in length, was identified by transcriptome sequencing analysis, and was named p53-inducible cancer-associated RNA transcript 1 (PICART1). PICART1 was found to be upregulated by p53 through a p53-binding site at -1808 to -1783 bp. In breast and colorectal cancer cells and tissues, PICART1 expression was found to be decreased. Ectopic expression of PICART1 suppressed the growth, proliferation, migration, and invasion of MCF7, MDA-MB-231 and HCT116 cells whereas silencing of PICART1 stimulated cell growth and migration. In these cells, the expression of PICART1 suppressed levels of p-AKT (Thr308 and Ser473) and p-GSK3ß (Ser9), and accordingly, ß-catenin, cyclin D1 and c-Myc expression were decreased, while p21Waf/cip1 expression was increased. Together these data suggest that PICART1 is a novel p53-inducible tumor-suppressor lncRNA, functioning through the AKT/GSK3ß/ß-catenin signaling cascade.