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.
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Linked Datasets (1)
RNA-seq in neurites and soma of primary hippocampal neurons isolated from P0 or P1 mice
Mus musculus24 data files
| File | Type | Size |
|---|---|---|
| 211012DIV18DendCtrl_S3_R1_001.fastq.gz | RNA-Seq | 320.2 MB |
| 211012DIV18DendCtrl_S3_R1_001.fastq.gz | RNA-Seq | 320.2 MB |
| 211012DIV18DendMG132_S4_R1_001.fastq.gz | RNA-Seq | 351.4 MB |
| 211012DIV18DendMG132_S4_R1_001.fastq.gz | RNA-Seq | 351.4 MB |
| 211012DIV18SomaCtrl_S1_R1_001.fastq.gz | RNA-Seq | 476.2 MB |
| 211012DIV18SomaCtrl_S1_R1_001.fastq.gz | RNA-Seq | 476.2 MB |
| 211012DIV18SomaMG132_S2_R1_001.fastq.gz | RNA-Seq | 385.4 MB |
| 211012DIV18SomaMG132_S2_R1_001.fastq.gz | RNA-Seq | 385.4 MB |
| 211115DIV17DendCtrl_S7_R1_001.fastq.gz | RNA-Seq | 496.1 MB |
| 211115DIV17DendCtrl_S7_R1_001.fastq.gz | RNA-Seq | 496.1 MB |
| 211115DIV17DendMG132_S8_R1_001.fastq.gz | RNA-Seq | 1.1 GB |
| 211115DIV17DendMG132_S8_R1_001.fastq.gz | RNA-Seq | 1.1 GB |
| 211115DIV17SomaCtrl_S5_R1_001.fastq.gz | RNA-Seq | 338.5 MB |
| 211115DIV17SomaCtrl_S5_R1_001.fastq.gz | RNA-Seq | 338.5 MB |
| 211115DIV17SomaMG132_S6_R1_001.fastq.gz | RNA-Seq | 229.8 MB |
| 211115DIV17SomaMG132_S6_R1_001.fastq.gz | RNA-Seq | 229.8 MB |
| 211122DIV17DendCtrl_S11_R1_001.fastq.gz | RNA-Seq | 368.7 MB |
| 211122DIV17DendCtrl_S11_R1_001.fastq.gz | RNA-Seq | 368.7 MB |
| 211122DIV17DendMG132_S12_R1_001.fastq.gz | RNA-Seq | 569.3 MB |
| 211122DIV17DendMG132_S12_R1_001.fastq.gz | RNA-Seq | 569.3 MB |
| 211122DIV17SomaCtrl_S9_R1_001.fastq.gz | RNA-Seq | 405.6 MB |
| 211122DIV17SomaCtrl_S9_R1_001.fastq.gz | RNA-Seq | 405.6 MB |
| 211122DIV17SomaMG132_S10_R1_001.fastq.gz | RNA-Seq | 926.3 MB |
| 211122DIV17SomaMG132_S10_R1_001.fastq.gz | RNA-Seq | 926.3 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.
RNA-seq in neurites and soma of primary hippocampal neurons isolated from P0 or P1 mice