Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.
Célia Alecki, Javeria Rizwan, Phuong Le, Suleima Jacob-Tomas, Mario Fernandez Comaduran, Morgane Verbrugghe, Jia Ming Stella Xu, Sandra Minotti, James Lynch, Jeetayu Biswas, Tad Wu, Heather D Durham, Gene W Yeo, Maria Vera
Nature communications · 2024 · Vol. 15 (1) · pp. 10796
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.
Linked datasets 1
RNA-seq in neurites and soma of primary hippocampal neurons isolated from P0 or P1 mice
Mus musculus
24 data files
| File | Type | Size |
|---|---|---|
| 211012DIV18DendCtrl_S3_R1_001.fastq.gz | RNA-Seq | 320.2 MB |
| 211012DIV18DendMG132_S4_R1_001.fastq.gz | RNA-Seq | 351.4 MB |
| 211012DIV18SomaCtrl_S1_R1_001.fastq.gz | RNA-Seq | 476.2 MB |
| 211012DIV18SomaMG132_S2_R1_001.fastq.gz | RNA-Seq | 385.4 MB |
| 211115DIV17DendCtrl_S7_R1_001.fastq.gz | RNA-Seq | 496.1 MB |
| 211115DIV17DendMG132_S8_R1_001.fastq.gz | RNA-Seq | 1.1 GB |
| 211115DIV17SomaCtrl_S5_R1_001.fastq.gz | RNA-Seq | 338.5 MB |
| 211115DIV17SomaMG132_S6_R1_001.fastq.gz | RNA-Seq | 229.8 MB |
| 211122DIV17DendCtrl_S11_R1_001.fastq.gz | RNA-Seq | 368.7 MB |
| 211122DIV17DendMG132_S12_R1_001.fastq.gz | RNA-Seq | 569.3 MB |
| 211122DIV17SomaCtrl_S9_R1_001.fastq.gz | RNA-Seq | 405.6 MB |
| 211122DIV17SomaMG132_S10_R1_001.fastq.gz | RNA-Seq | 926.3 MB |
| SRR19078900_GSM6103843 | RNA-Seq | 569.0 MB |
| SRR19078901_GSM6103841 | RNA-Seq | 926.0 MB |
| SRR19078902_GSM6103839 | RNA-Seq | 368.0 MB |
| SRR19078903_GSM6103837 | RNA-Seq | 405.0 MB |
| SRR19078904_GSM6103835 | RNA-Seq | 1.1 GB |
| SRR19078905_GSM6103833 | RNA-Seq | 229.0 MB |
| SRR19078906_GSM6103831 | RNA-Seq | 496.0 MB |
| SRR19078907_GSM6103829 | RNA-Seq | 338.0 MB |
| SRR19078908_GSM6103827 | RNA-Seq | 351.0 MB |
| SRR19078909_GSM6103826 | RNA-Seq | 385.0 MB |
| SRR19078910_GSM6103823 | RNA-Seq | 320.0 MB |
| SRR19078911_GSM6103821 | RNA-Seq | 476.0 MB |
Potentially related datasets 2
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
Analysis pipelines 1
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE202202 RNA-seq Data Processing geo_data_processing | RNA-seq | 4 | GSE202202 |
Funding 15 grants
| Grant | Funder |
|---|---|
| U24 HG009889 | NHGRI NIH HHS (United States) |
| R01 HG004659 | NHGRI NIH HHS (United States) |
| RF1 MH126719 | NIMH NIH HHS (United States) |
| R01 HG011864 | NHGRI NIH HHS (United States) |
| R01 NS103172 | NINDS NIH HHS (United States) |
| U41 HG009889 | NHGRI NIH HHS (United States) |
| 300232 | Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec) |
| MH126719 | U.S. Department of Health & Human Services | National Institutes of Health (NIH) |
| HG009889 | U.S. Department of Health & Human Services | National Institutes of Health (NIH) |
| HG011864 | U.S. Department of Health & Human Services | National Institutes of Health (NIH) |
| PJT-186141 | Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) |
| HG004659 | U.S. Department of Health & Human Services | National Institutes of Health (NIH) |
| Hudson Translational Team Grant | ALS Society of Canada (ALS Canada) |
| 2022-ALS Discovery Grant | ALS Society of Canada (ALS Canada) |
| P30 CA008748 | NCI NIH HHS (United States) |