Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

Loveland, A.B.; Svidritskiy, Egor; Susorov, Denis; Lee, Soojin; Park, Alexander; Zvornicanin, Sarah N.; Demo, Gabriel; Gao, Fen‐Biao; Коростелев, А.A.

doi:10.1038/s41467-022-30418-0

Cited by 49 publications

(56 citation statements)

References 100 publications

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“…The 8×Arg-His repeats are reminiscent of dipeptide repeat expansions in the human C9ORF72 gene, which cause neurological disease in humans [63][64][65] . Alternate initiation in the C9ORF72 ORF results in translation of extended Arg-Gly and Arg-Pro repeats, which stall ribosomes and cause premature termination in a length dependent manner, with 20× dipeptide repeats being the minimal length required to to stall ribosomes 66,67 . Unsurprisingly, we do not observe marked effects from 8× Arg-Gly or Arg-Pro in our assay, as 10× repeats of these dipeptides do not cause premature termination 66 .…”

Section: Discussionmentioning

confidence: 99%

A nascent peptide code for translational control of mRNA stability in human cells

2022

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Stability of eukaryotic mRNAs is associated with their codon, amino acid, and GC content. Yet, coding sequence motifs that predictably alter mRNA stability in human cells remain poorly defined. Here, we develop a massively parallel assay to measure mRNA effects of thousands of synthetic and endogenous coding sequence motifs in human cells. We identify several families of simple dipeptide repeats whose translation triggers mRNA destabilization. Rather than individual amino acids, specific combinations of bulky and positively charged amino acids are critical for the destabilizing effects of dipeptide repeats. Remarkably, dipeptide sequences that form extended β strands in silico and in vitro slowdown ribosomes and reduce mRNA levels in vivo. The resulting nascent peptide code underlies the mRNA effects of hundreds of endogenous peptide sequences in the human proteome. Our work suggests an intrinsic role for the ribosome as a selectivity filter against the synthesis of bulky and aggregation-prone peptides.

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Section: Discussionmentioning

confidence: 99%

A nascent peptide code for translational control of mRNA stability in human cells

2022

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“…We also validated that this shift in rRNA occurs within cortical neurons in postmortem C9ORF72 ALS/FTD tissue using immunohistochemistry (IHC) (Figure S4B). This increased N/C ratio of rRNA, which suggests impaired ribosomal homeostasis, likely contributes to the previously described reduced level of translation in poly-GRcontaining cells (Figure S3L) (Hartmann et al, 2018;Lee et al, 2016;Loveland et al, 2022;Zhang et al, 2018b).…”

Section: Characterization Of the Interaction Between C9 R-dprs And Rn...mentioning

confidence: 60%

CLIP-Seq Analysis Enables the Design of Ribosomal RNA Bait Oligonucleotides That Protect AgainstC9ORF72ALS/FTD-Associated Poly-GR Pathophysiology

Ortega

Sasselli

Boccitto

et al. 2022

Preprint

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Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind to low complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remains unclear. We used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA 'bait' oligonucleotides restore poly-GR-associated ribosomal deficits in cells and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal disfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms.

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“…Some of the C9-ALS and C9-FTD-associated DPR proteins (poly(PR) and poly(GR)) bind to ribosomal proteins and translation elongation factors, and impair global translation (87)(88)(89). Specifically, these DPRs bind to the ribosomal tunnel and block translation, potentially explaining their toxicity in C9-ALS and C9-FTD (90). We therefore hypothesize that the broad upregulation of gene encoding translation system components in C9-ALS excitatory neurons represents a compensatory response to this impairment of translation.…”

Section: Discussionmentioning

confidence: 99%

Divergent impacts ofC9orf72repeat expansion on neurons and glia in ALS and FTD

Jaiswal

Chien

et al. 2022

Preprint

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Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are strongly influenced by inherited genetic variation, but environmental and epigenetic factors also play key roles in the course of these diseases. A hexanucleotide repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of ALS and FTD. To determine the cellular alterations associated with the C9 repeat expansion, we performed single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem samples of motor and frontal cortices from C9-ALS and C9-FTD donors. We found pervasive alterations of gene expression across multiple cortical cell types in C9-ALS, with the largest number of affected genes in astrocytes and excitatory neurons. Astrocytes increased expression of markers of activation and pathways associated with structural remodeling. Excitatory neurons in upper and deep layers increased expression of genes related to proteostasis, metabolism, and protein expression, and decreased expression of genes related to neuronal function. Epigenetic analyses revealed concordant changes in chromatin accessibility, histone modifications, and gene expression in specific cell types. C9-FTD patients had a distinct pattern of changes, including loss of neurons in frontal cortex and altered expression of thousands of genes in astrocytes and oligodendrocyte-lineage cells. Overall, these findings demonstrate a context-dependent molecular disruption in C9-ALS and C9-FTD, resulting in distinct effects across cell types, brain regions, and disease phenotypes.

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Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

Cited by 49 publications

References 100 publications

A nascent peptide code for translational control of mRNA stability in human cells

A nascent peptide code for translational control of mRNA stability in human cells

CLIP-Seq Analysis Enables the Design of Ribosomal RNA Bait Oligonucleotides That Protect AgainstC9ORF72ALS/FTD-Associated Poly-GR Pathophysiology

Divergent impacts ofC9orf72repeat expansion on neurons and glia in ALS and FTD

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