scholarly journals C9orf72 Dipeptide Repeats Inhibit UPF1-Mediated RNA Decay Independent of Stress Granule Formation

2019 ◽  
Author(s):  
Yu Sun ◽  
Aziz Eshov ◽  
Junjie U. Guo
Keyword(s):  
Cultured Cells ◽  
Ectopic Expression ◽  
Stress Granule ◽  
Rna Decay ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Repeat Region ◽  
Granule Formation ◽  
Nonsense Mediated Decay ◽  
Rna Surveillance ◽  
Lateral Sclerosis

ABSTRACTExpansion of an intronic (GGGGCC)n repeat region within the C9orf72 gene is a major cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A pathological hallmark in c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of RNA surveillance pathways in normal cells. Here we show that nonsense-mediated decay (NMD) and other RNA decay mechanisms involving upstream frameshift 1 (UPF1), collectively referred to as UPF1-mediated RNA decay (UMD), are broadly inhibited in c9ALS/FTD brains. These effects are recapitulated in cultured cells by the ectopic expression of arginine-rich dipeptide repeats (DPRs), poly(GR) and poly(PR). Despite these two DPRs causing the recruitment of UPF1 to stress granules, stress granule formation is neither sufficient nor necessary for UMD inhibition. Our results suggest that UMD inhibition may accelerate the accumulation of deleterious RNAs and polypeptides in c9ALS/FTD.

scholarly journals Ubiquitination is essential for recovery of cellular activities after heat shock

Science ◽  
2021 ◽  
Vol 372 (6549) ◽  
pp. eabc3593
Author(s):  
Brian A. Maxwell ◽  
Youngdae Gwon ◽  
Ashutosh Mishra ◽  
Junmin Peng ◽  
Haruko Nakamura ◽  
...  
Keyword(s):  
Heat Stress ◽  
Cultured Cells ◽  
Nucleocytoplasmic Transport ◽  
Stress Granule ◽  
Eukaryotic Cells ◽  
Granule Formation ◽  
Cellular Processes ◽  
Specific Proteins ◽  
Global Increase ◽  
As Stress

Eukaryotic cells respond to stress through adaptive programs that include reversible shutdown of key cellular processes, the formation of stress granules, and a global increase in ubiquitination. The primary function of this ubiquitination is thought to be for tagging damaged or misfolded proteins for degradation. Here, working in mammalian cultured cells, we found that different stresses elicited distinct ubiquitination patterns. For heat stress, ubiquitination targeted specific proteins associated with cellular activities that are down-regulated during stress, including nucleocytoplasmic transport and translation, as well as stress granule constituents. Ubiquitination was not required for the shutdown of these processes or for stress granule formation but was essential for the resumption of cellular activities and for stress granule disassembly. Thus, stress-induced ubiquitination primes the cell for recovery after heat stress.

scholarly journals Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization

2021 ◽  
Author(s):  
Anna-Leigh Brown ◽  
Oscar Wilkins ◽  
Matthew Keuss ◽  
Sarah Hill ◽  
Matteo Zanovello ◽  
...  
Keyword(s):  
Rna Binding ◽  
Cultured Cells ◽  
Rna Binding Protein ◽  
Protein Loss ◽  
Nonsense Mediated Decay ◽  
Cryptic Exon ◽  
Risk Variants ◽  
Promising Therapeutic Target ◽  
Increase Risk ◽  
Lateral Sclerosis

Abstract Variants within the UNC13A gene have long been known to increase risk of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here, we show that TDP-43 depletion induces robust inclusion of a cryptic exon (CE) within UNC13A, a critical synaptic gene, resulting in nonsense-mediated decay and protein loss. Strikingly, two common polymorphisms strongly associated with ALS/FTD risk directly alter TDP-43 binding within the CE or downstream intron, increasing CE inclusion in cultured cells and in patient brains. Our findings, which are the first to demonstrate a genetic link specifically between loss of TDP-43 nuclear function and disease, reveal both the mechanism by which UNC13A variants exacerbate the effects of decreased nuclear TDP-43 function, and provide a promising therapeutic target for TDP-43 proteinopathies.

scholarly journals Common ALS/FTD risk variants in UNC13A exacerbate its cryptic splicing and loss upon TDP-43 mislocalization

2021 ◽  
Author(s):  
Anna-Leigh Brown ◽  
Oscar G. Wilkins ◽  
Matthew J. Keuss ◽  
Sarah E. Hill ◽  
Matteo Zanovello ◽  
...  
Keyword(s):  
Rna Binding ◽  
Cultured Cells ◽  
Rna Binding Protein ◽  
Protein Loss ◽  
Nonsense Mediated Decay ◽  
Cryptic Exon ◽  
Risk Variants ◽  
Promising Therapeutic Target ◽  
Increase Risk ◽  
Lateral Sclerosis

Variants within the UNC13A gene have long been known to increase risk of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-43. Here, we show that TDP-43 depletion induces robust inclusion of a cryptic exon (CE) within UNC13A, a critical synaptic gene, resulting in nonsense-mediated decay and protein loss. Strikingly, two common polymorphisms strongly associated with ALS/FTD risk directly alter TDP-43 binding within the CE or downstream intron, increasing CE inclusion in cultured cells and in patient brains. Our findings, which are the first to demonstrate a genetic link specifically between loss of TDP-43 nuclear function and disease, reveal both the mechanism by which UNC13A variants exacerbate the effects of decreased nuclear TDP-43 function, and provide a promising therapeutic target for TDP-43 proteinopathies.

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