| Autor: |
Steven Finkbeiner, Neal A.L. Cody, Kari L. Server, Ashkan Javaherian, Eric Lécuyer, Sara Broski, Gene W. Yeo, Amit Fulzele, Sebastian Markmiller, Shashank Sathe, Eric J. Bennett, Thai B. Nguyen |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
SSRN Electronic Journal. |
| ISSN: |
1556-5068 |
| Popis: |
Neurodegeneration-associated mutations affect the dynamics of transient cytoplasmic stress granules (SGs). However, it is unclear if and how aberrant SG behavior is linked to the downstream formation of protein aggregates and other molecular defects that persist after stress subsides. Here, we sought to assess the impact of stress and genetic mutations associated with Amyotrophic Lateral Sclerosis (ALS) on the global mRNA localization landscape of human pluripotent stem cell-derived motor neurons (PSC-MNs). Using subcellular fractionation with RNA sequencing (CeFra-seq) and quantitative proteomics, we found that transient stress leads to a widespread reshaping of mRNA and protein localization that recapitulates key molecular phenotypes of ALS. While the substantial reorganization of the global mRNA localization landscape was largely reversible in wild type PSC-MNs, we find that cells harboring ALS-linked mutations in HNRNPA2B1 were unable to recover and displayed a delayed-onset increase in neuronal cell death in response to stress. Our results highlight subcellular RNA and protein distribution as key predictive features of stress-induced molecular mechanisms in the formation of molecular disease pathology of ALS. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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