Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis Journal Article
| Authors: | Alecki, C.; Rizwan, J.; Le, P.; Jacob-Tomas, S.; Comaduran, M. F.; Verbrugghe, M.; Xu, J. M. S.; Minotti, S.; Lynch, J.; Biswas, J.; Wu, T.; Durham, H. D.; Yeo, G. W.; Vera, M. |
| Article Title: | Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis |
| Abstract: | Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhances HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites is impaired by depleting fused in sarcoma—an amyotrophic lateral sclerosis-related protein—in cultured spinal cord mouse motor neurons or by expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration. © The Author(s) 2024. |
| Keywords: | controlled study; unclassified drug; human cell; genetics; nonhuman; protein localization; animal cell; mouse; animal; cytology; metabolism; animals; mice; benzyloxycarbonylleucylleucylleucinal; fluorescence; protein; gene locus; proteomics; morphology; rna; amino acid sequence; messenger rna; protein synthesis; rna, messenger; spinal cord; motor neurons; dactinomycin; rna translation; protein biosynthesis; heat shock protein 90; cellular distribution; polysome; microtubule assembly; fluorescence microscopy; down regulation; upregulation; heat shock protein 70; protein folding; molecular biology; microtubule; microtubules; peptide synthesis; rna extraction; heat shock; hsp70 heat-shock proteins; induced pluripotent stem cells; dendrite; dendrites; motoneuron; reoxygenation; chaperone; hippocampus; rna-binding protein fus; molecular chaperones; protein homeostasis; synaptic transmission; protein quality; gene ontology; pathogen; heat shock protein 110; microtubule associated protein 2; calcium calmodulin dependent protein kinase ii; puromycin; anisomycin; hsc70 heat-shock proteins; induced pluripotent stem cell; proteotoxic stress; humans; human; article; rna sequencing; protein refolding; differential expression analysis; differential gene expression; proteostasis; heat shock cognate protein 70; maltose binding protein; rna binding protein fus; protein misfolding; calcium calmodulin dependent protein kinase ii alpha; heat shock protein 90ab; heterogeneous nuclear ribonucleoprotein a2; heterogeneous nuclear ribonucleoprotein b1; heterogeneous nuclear ribonucleoprotein group a b; fus protein, human; fus protein, mouse; hspa8 protein, human; hspa8 protein, mouse; proteotoxicity |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-12-30 |
| Start Page: | 10796 |
| Language: | English |
| DOI: | 10.1038/s41467-024-55055-7 |
| PUBMED: | 39737952 |
| PROVIDER: | scopus |
| PMCID: | PMC11685665 |
| DOI/URL: | |
| Notes: | Source: Scopus |
