How villains are made: The translation of dipeptide repeat proteins in C9ORF72-ALS/FTD

Spijker, Heleen M van 't; Almeida, Sandra

doi:10.1016/j.gene.2023.147167

Cited by 7 publications

(6 citation statements)

References 85 publications

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“…The identification of DPRs that generated via RAN translation from the G4C2 hexanucleotide repeat expansions in the C9orf72 gene greatly deepen our understanding of the cause of ALS and FTD. [31,32] However, the molecular mechanism underlying how DPRs cause cellular toxicity is less clear. Even though many pathways have been associated with PRn toxicity, nuclear accumulation of PRn is more toxic and lessening the nuclear accumulation of PRn can drastically reduce its neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)‐Induced Cell Death

Chen,

Guo,

Guo

et al. 2024

Advanced Biology

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Repeat dipeptides such as poly(proline‐arginine) (polyPR) are generated from the hexanucleotide GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are often considered as the genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the study, fluorescein isothiocyanate (FITC) labeled PR20 is used to investigate PR20‐induced cell death. The findings reveal that the cell death induced by PR20 is dependent on its nuclear distribution and can be blocked by a nuclear import inhibitor called importazole. Further investigation reveals that BRD4 inhibitors, such as JQ‐1 and I‐BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. Mechanistically, the inhibition of BRD4 leads to an increase in the expression of numerous histones, resulting in the accumulation of histones in the cytoplasm. These cytoplasmic histones associate with PR20 and limit its distribution within the nucleus. Notably, the ectopic expression of histones alone is enough to confer protection to cells treated with PR20. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20‐induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)‐Induced Cell Death

Chen,

Guo,

Guo

et al. 2024

Advanced Biology

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“…The third candidate mechanism proposes that one or more of the five DPR-containing polypeptides generated by RAN translation of mutant C9ORF72 are toxic [17][18][19] . RAN-translated DPRs have been detected in multiple neurological diseases with repeat expansions and are implicated in pathogenesis [18,19] .…”

Section: Discussionmentioning

confidence: 99%

“…Concurrently, other studies have implicated the accumulation of dipeptide repeat proteins (DPRs) [17] produced by repeat-associated non-ATG (RAN) translation [17][18][19] . GPn is produced by translation in both forward and reverse directions.…”

Section: Introductionmentioning

confidence: 96%

Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats

Okekenwa,

Tsai,

Dooley

et al. 2023

Preprint

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Expansion of a hexanucleotide repeat in a noncoding region of the C9ORF72 gene is responsible for a significant fraction of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) cases, but identifying specific toxic gene products and mechanisms has been difficult. Pathogenesis was proposed to involve the production of toxic RNA species and/or accumulation of toxic dipeptide repeats (DPRs), but distinguishing between these mechanisms has been challenging. In this study, we first use complementary model systems for analyzing pathogenesis in adult-onset neurodegenerative diseases to characterize the pathogenicity of DPRs produced by Repeat Associated Non-ATG (RAN) translation of C9ORF72 in specific cellular compartments: isolated axoplasm and giant synapse from the squid. Results showed selective axonal and presynaptic toxicity of GP-DPRs, independent of associated RNA. These effects involved downstream ASK1 signaling pathways that affect fast axonal transport and synaptic function, a pathogenic mechanism shared with other mutant proteins associated with familial ALS, like SOD1 and FUS. These pathways are sufficient to produce the “dying-back” axonopathy seen in ALS. However, other mutant genes (e.g., SOD1) that activate this mechanism rarely produce FTD. When parallel studies in primary motor neurons from rats were conducted, an additional pathogenic mechanism was revealed. The GR- and PR-DPRs, which had no effect on axonal transport or synaptic transmission, were found to disrupt the nuclei of transfected neurons, leading to “dying-forward” neuropathy. All C9-DRP-mediated toxic effects observed here are independent of whether the corresponding mRNAs contained hexanucleotide repeats or alternative codons. These studies establish the divergent toxicity of C9-DPRs that cause neurodegeneration in ALS and FTD, suggesting that these two independent pathogenic mechanisms may contribute to disease heterogeneity and/or synergize on disease progression in C9ORF72 patients with both ALS and FTD symptoms.Abstract FigureGraphic AbstractActivation of protein kinases and inhibition of axonal transport, synaptic transmission, and nuclear structure are toxic effects common to unrelated FALS-related gene products.FALS-related mutant forms of SOD1 (mSOD1), FUS (mFUS), and C9-GP-DPRs (GP(n)) activate specific ASK1-MAPK pathway. Within axons, active ASK1-p38 pathway phosphorylates various substrates, including conventional kinesin, leading to the inhibition of fast axonal transport mediated by the translocation of this motor protein along microtubules. ASK1 can also inhibit synaptic transmission via JNK activation. Both pathways cause reductions in the availability of critical synaptic cargoes, synaptic dysfunction, and “dying-back” degeneration of neurons. On the other hand, C9-PR and GR-DPRs (PR(n)and GR(n)) activate other pathways, leading to aberrant alterations in nuclear structure and function and “dying-forward” degeneration of neurons, consistent with reports of transcriptional changes and activation of apoptosis in ALS.

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“…Healthy individuals have less than 30 GGGGCC repeats, but in ALS patients, GGGGCC sequences can be amplified hundreds or thousands of times. The C9orf72 mutation appears to drive the pathogenesis of ALS through the loss of normal function of C9orf72 and the acquisition of toxic effects caused by the repeated amplification ( Vant Spijker and Almeida, 2023 ), which leads to the RNA amplification, the dipeptide repeat proteins aggregation and the C9orf72 haploid dysfunction. The RNAs containing (GGGGCC)n and the translation product the dipeptide repeat protein (GGGGCC)n are cytotoxic and can interfere with UPS and affect the protein degradation.…”

Section: Imbalance Of Protein Homeostasis In Neuronsmentioning

confidence: 99%

Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis

Wan

2023

Front. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that leads to the massive loss of motor neurons in cerebrum, brain stem and spinal cord. It affects not only motor neurons but also other neurons and glial cells, resulting in the progressive muscle atrophy, the severe disability and the eventual death due to the respiratory failure. The pathogenesis of ALS is not fully understood. Currently, several factors are considered to be involved in the pathogenesis of ALS, such as genetic factors, imbalances in protein homeostasis, RNA metabolism disorders, mitochondrial dysfunctions, glutamate-mediated excitatory toxicities and intra-neuronal material transport disorders in neurons. The study of genetic mutations related to ALS pathogenesis will link the molecular and cellular mechanisms of the disease, thus enhancing the understanding of its occurrence and progression, thereby providing new insights for the pathogenesis of ALS. This review summarizes the current insights in the molecular genetic pathogenesis of ALS.

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How villains are made: The translation of dipeptide repeat proteins in C9ORF72-ALS/FTD

Cited by 7 publications

References 85 publications

Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)‐Induced Cell Death

Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)‐Induced Cell Death

Divergent Molecular Pathways for Toxicity of Selected Mutant C9ORF72-derived Dipeptide Repeats

Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis

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