Shekhar Shashank, Tracy Charles, Lidsky Peter V, Andino Raul, Wert Katherine J, Krämer Helmut
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, USA.
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
Nat Commun. 2025 Jan 2;16(1):252. doi: 10.1038/s41467-024-55576-1.
Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by eIF2α phosphorylation-dependent elevated levels of the ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain.
感觉障碍已被确定为痴呆症的重要风险因素，但其潜在的分子机制尚不清楚。在不同的感觉输入缺失的果蝇模型中，我们观察到大脑深处非自主性诱导整合应激反应（ISR），这表现为eIF2α磷酸化依赖的ISR效应因子ATF4和XRP1水平升高。然而，与经典ISR不同的是，ATF4和XRP1转录因子在富含RNA以及应激颗粒标志物Caprin、FMR1和p62的胞质颗粒中富集，并且对于失明果蝇恢复视力后是可逆的。ATF4和XRP1转录因子的胞质抑制减弱了其下游靶点的表达，包括在慢性细胞应激期间激活的细胞死亡途径的基因，因此构成了一种慢性应激保护反应（CSPR）。在先天性或退行性失明小鼠模型的丘脑和海马体中，同时含有p62和ATF4的胞质颗粒也很明显。这些数据表明感觉输入缺失与抑制应激反应之间存在保守联系，这对大脑中的蛋白质质量控制至关重要。
