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

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. We found that a unique cell selection mechanism based on relative fitness comparison between neurons is able to target and remove aberrantly active neurons generated by heterologous human amyloid-ß in Drosophila. Sustained neuronal activity is sufficient to compromise neuronal fitness and upregulate the expression of the low fitness indicators FlowerLoseB and Azot in the fly. Conversely, forced silencing of neurons restores brain fitness and reduces amyloid-ß-induced cell death. The manipulation of this cell selection process, which was already proved to be conserved in humans, might be a promising new avenue to treat Alzheimer's.

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-ß (Aß) peptides triggers a complex cascade of pathological events underlying neuronal death, whose details are not yet completely understood. Our laboratory recently discovered that cell competition may play a protective role against AD by eliminating less fit neurons from the brain of Aß-transgenic flies. Loss of Aß-damaged neurons through fitness comparison with healthy counterparts is beneficial for the organism, delaying cognitive decline and motor disability. In this Review, we introduce the molecular mechanisms of cell competition, including seminal works on the field and latest advances regarding genetic triggers and effectors of cell elimination. We then describe the biological relevance of competition in the nervous system and discuss how competitive interactions between neurons may arise and be exacerbated in the context of AD. Selection of neurons through fitness comparison is a promising, but still emerging, research field that may open new avenues for the treatment of neurological disorders.

Culling Less Fit Neurons Protects against Amyloid-ß-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. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-ß42 peptide and showed that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We demonstrated that removal of less fit neurons delays ß-amyloid-induced brain damage and protects against cognitive and motor decline, suggesting that contrary to common knowledge, neuronal death may have a beneficial effect in AD.

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. Here, we generated a Drosophila Xbp1 deletion mutant (Excision101) lacking both HR2 and C-terminal region, but not the Ire1 splicing site. We show that Ire1-dependent splicing of Xbp1 mRNA is reduced, but not abolished in Excision101. Our results suggest the existence of additional mechanisms for ER membrane targeting of Xbp1 mRNA that are independent of the C-terminal domain of Drosophila Xbp1unspliced.

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. This process was called RIDD (regulated Ire1-dependent decay), but its physiological significance remained poorly characterized beyond cell culture systems. Here we review several recent studies that have highlighted the physiological roles of RIDD in specific biological paradigms, such as photoreceptor differentiation in Drosophila or mammalian liver and endocrine pancreas function. These studies demonstrate the importance of RIDD in tissues undergoing intense secretory function and highlight the physiologic role of RIDD during UPR activation in cells and organisms.

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. However, these defects are not observed in Xbp1 mutant photoreceptors. Ire1 mutant retinas have higher mRNA levels for targets of regulated Ire1-dependent decay (RIDD), including for the fatty acid transport protein (fatp). Importantly, the downregulation of fatp by RNAi rescues the rhodopsin-1 delivery defects observed in Ire1 mutant photoreceptors. Our results show that the role of Ire1 during photoreceptor differentiation is independent of Xbp1 function and demonstrate the physiological relevance of the RIDD mechanism in this specific paradigm.