An image-based multiplex autophagosome RNAi screen targeting all Rab GTPases as well as their GAPs and GEFs identifies the Rab GEF SMCR8 as multifaceted autophagy modulator, which regulates kinase activity and gene expression of ULK1.
A drug-like molecule called ISRIB, which activates the translation initiation factor eIF2B, antagonizes stress responses as diverse as protein misfolding and nutrient deprivation, and restores protein synthesis, enhancing memory.
Super-resolution imaging reveals that the microtubule-associated protein Tau regulates the Fyn kinase organisation in dendrites, and that the frontotemporal dementia mutant Tau promotes aberrant Fyn clustering, potentially leading to synaptic dysfunction.
Cellular and genetic approaches reveal that exposure of a normally buried nuclear export signal (NES)-like sequence mediates export of ALS-linked mutant and misfolded wild-type SOD1 to the cytoplasm by CRM1.
In neuronal mitophagy, Parkin and OPTN induce efficient sequestration of damaged somal mitochondria into autophagosomes, but slow turnover via lysosomal acidification may be a point of vulnerability for the cell.
Impaired lysosomal acidification results in retention of iron inside lysosomes, triggering functional iron deficiency, dysfunctional mitochondria (especially mtDNA loss), and inflammation in vivo in a mouse model of lysosomal disease.