| Experiment Id | GSE269588 | Name | Plekhg5 regulates the unconventional secretion of Sod1 by presynaptic secretory autophagy |
| Experiment Type | RNA-Seq | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2024-09-09 |
| description | Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated protein Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into the intermembrane space of autophagosomes which fuse with secretory lysosomal-related organelles (LROs). Deletion of Plekhg5 in mice disrupts the secretion of these LROs causing Sod1 accumulation at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human isogenic iPSC-derived motoneurons we show an impaired secretion of ALS-linked SOD1D90A, which coincided with a reduced PLEKHG5 expression. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway. To investigate the impact of Plekhg5 on the phenotype of SOD1-G93A mice, we crossed Plekhg5-deficient mice with SOD1-G93A expressing mice. Total RNA was isolated from spinal cord tissues of 7 months-old mice and we performed gene expression profiling analysis with RNAseq data from wildtype (control) mice, Plekhg5-deficient mice, SOD1-G93A mice, and Plekhg5-deficient SOD1-G93A mice. |
