| Title: |
4E-BP1 Protects Neurons from Misfolded Protein Stress and Parkinson's Disease Toxicity by Inducing the Mitochondrial Unfolded Protein Response |
| Authors: |
Dastidar, Somasish Ghosh; Pham, Michael T; Mitchell, Matthew B; Yeom, Steven G; Jordan, Sarah; Chang, Angela; Sopher, Bryce L; La Spada, Albert R |
| Source: |
Journal of Neuroscience, vol 40, iss 45 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2020 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
32 Biomedical and Clinical Sciences (for-2020); 3209 Neurosciences (for-2020); Aging (rcdc); Brain Disorders (rcdc); Parkinson's Disease (rcdc); Neurosciences (rcdc); Neurodegenerative (rcdc); Neurological (hrcs-hc); Adaptor Proteins; Signal Transducing (mesh); Animals (mesh); Animals; Newborn (mesh); Brefeldin A (mesh); Cell Cycle Proteins (mesh); Female (mesh); Male (mesh); Mice (mesh); Mice; Transgenic (mesh); Mitochondria (mesh); Neurons (mesh); Parkinson Disease; Secondary (mesh); Primary Cell Culture (mesh); Protein Biosynthesis (mesh); Protein Synthesis Inhibitors (mesh); Protein Unfolding (mesh); Proteostasis Deficiencies (mesh); Rotenone (mesh) |
| Time: |
8734 - 8745 |
| Description: |
Decline of protein quality control in neurons contributes to age-related neurodegenerative disorders caused by misfolded proteins. 4E-BP1 is a key node in the regulation of protein synthesis, as activated 4E-BP1 represses global protein translation. Overexpression of 4E-BP1 mediates the benefits of dietary restriction and can counter metabolic stress, and 4E-BP1 disinhibition on mTORC1 repression may be neuroprotective; however, whether 4E-BP1 overexpression is neuroprotective in mammalian neurons is yet to be fully explored. To address this question, we generated 4E-BP1-overexpressing transgenic mice and confirmed marked reductions in protein translation in 4E-BP1-overexpressing primary neurons. After documenting that 4E-BP1-overexpressing neurons are resistant to proteotoxic stress elicited by brefeldin A treatment, we exposed primary neurons to three different Parkinson's disease (PD)-linked toxins (rotenone, maneb, or paraquat) and documented significant protection in neurons from newborn male and female 4E-BP1-OE transgenic mice. We observed 4E-BP1-dependent upregulation of genes encoding proteins that comprise the mitochondrial unfolded protein response, and noted 4E-BP1 overexpression required activation of the mitochondrial unfolded protein response for neuroprotection against rotenone toxicity. We also tested whether 4E-BP1 could prevent α-synuclein neurotoxicity by treating 4E-BP1-overexpressing primary neurons with α-synuclein preformed fibrils, and we observed marked reductions in α-synuclein aggregation and neurotoxicity, thus validating that 4E-BP1 is a powerful suppressor of PD-linked pathogenic insults. Our results indicate that increasing 4E-BP1 expression or enhancing 4E-BP1 activation can robustly induce the mitochondrial unfolded protein response and thus could be an appealing strategy for treating a variety of neurodegenerative diseases, including especially PD.SIGNIFICANCE STATEMENT In neurodegenerative disease, misfolded proteins accumulate and overwhelm normal systems of homeostasis and ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt75r9p101; https://escholarship.org/uc/item/75r9p101; https://escholarship.org/content/qt75r9p101/qt75r9p101.pdf |
| DOI: |
10.1523/jneurosci.0940-20.2020 |
| Availability: |
https://escholarship.org/uc/item/75r9p101; https://escholarship.org/content/qt75r9p101/qt75r9p101.pdf; https://doi.org/10.1523/jneurosci.0940-20.2020 |
| Rights: |
CC-BY-NC-SA |
| Accession Number: |
edsbas.7D70D9BD |
| Database: |
BASE |