Neuronal Selection Based on Relative Fitness Comparison Detects and Eliminates Amyloid-β-Induced Hyperactive Neurons in .

During adult life, damaged but viable neurons can accumulate in the organism, creating increasingly heterogeneous and dysfunctional neural circuits. One intriguing example is the aberrant increased activity of cerebral networks detected in vulnerable brain regions during preclinical stages of Alzheimer's disease. The pathophysiological contribution of these early functional alterations to the progression of Alzheimer's disease is uncertain.

Emerging links between cell competition and Alzheimer's disease.

Alzheimer's disease (AD) causes a progressive loss of memory and other cognitive functions, which inexorably debilitates patients. There is still no cure for AD and effective treatments to delay or revert AD are urgently needed. On a molecular level, the excessive accumulation of amyloid-β (Aβ) peptides triggers a complex cascade of pathological events underlying neuronal death, whose details are not yet completely understood.

Culling Less Fit Neurons Protects against Amyloid-β-Induced Brain Damage and Cognitive and Motor Decline.

Alzheimer's disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain.

Ire1 mediated mRNA splicing in a C-terminus deletion mutant of Drosophila Xbp1.

The Unfolded Protein Response is a homeostatic mechanism that permits eukaryotic cells to cope with Endoplasmic Reticulum (ER) stress caused by excessive accumulation of misfolded proteins in the ER lumen. The more conserved branch of the UPR relies on an ER transmembrane enzyme, Ire1, which, upon ER stress, promotes the unconventional splicing of a small intron from the mRNA encoding the transcription factor Xbp1. In mammals, two specific regions (the hydrophobic region 2--HR2--and the C-terminal translational pausing site) present in the Xbp1unspliced protein mediate the recruitment of the Xbp1 mRNA-ribosome-nascent chain complex to the ER membrane, so that Xbp1 mRNA can be spliced by Ire1.

Physiological roles of regulated Ire1 dependent decay.

Inositol-requiring enzyme 1 (Ire1) is an important transducer of the unfolded protein response (UPR) that is activated by the accumulation of misfolded proteins in the endoplamic reticulum (ER stress). Activated Ire1 mediates the splicing of an intron from the mRNA of Xbp1, causing a frame-shift during translation and introducing a new carboxyl domain in the Xbp1 protein, which only then becomes a fully functional transcription factor. Studies using cell culture systems demonstrated that Ire1 also promotes the degradation of mRNAs encoding mostly ER-targeted proteins, to reduce the load of incoming ER "client" proteins during ER stress.

Xbp1-independent Ire1 signaling is required for photoreceptor differentiation and rhabdomere morphogenesis in Drosophila.

The unfolded protein response (UPR) is composed by homeostatic signaling pathways that are activated by excessive protein misfolding in the endoplasmic reticulum. Ire1 signaling is an important mediator of the UPR, leading to the activation of the transcription factor Xbp1. Here, we show that Drosophila Ire1 mutant photoreceptors have defects in the delivery of rhodopsin-1 to the rhabdomere and in the secretion of Spacemaker/Eyes Shut into the interrhabdomeral space.