Toxic dipeptide-repeat (DPR) proteins are produced from expanded G4C2 repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.
- MeSH
- amyotrofická laterální skleróza * genetika metabolismus MeSH
- dipeptidy metabolismus MeSH
- elektronová kryomikroskopie MeSH
- frontotemporální demence * genetika metabolismus MeSH
- lidé MeSH
- protein C9orf72 genetika metabolismus MeSH
- proteiny genetika metabolismus MeSH
- ribozomy metabolismus MeSH
- transferasy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- amyotrofická laterální skleróza * genetika MeSH
- antisense oligonukleotidy terapeutické užití MeSH
- časná diagnóza MeSH
- celogenomová asociační studie MeSH
- DNA MeSH
- genom lidský MeSH
- lidé MeSH
- lidské chromozomy, pár 9 MeSH
- mutace MeSH
- neuroglie MeSH
- protein C9orf72 MeSH
- proteinopatie TDP-43 MeSH
- regulace genové exprese MeSH
- sekvenční analýza DNA MeSH
- Check Tag
- lidé MeSH
BACKGROUND: The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously. OBJECTIVE: To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME. RESULTS: We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions. CONCLUSION: C9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence.
- MeSH
- dospělí MeSH
- expanze repetic DNA * MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- lidé středního věku MeSH
- lidé MeSH
- mozek patologie MeSH
- myoklonické epilepsie progresivní genetika patologie patofyziologie psychologie MeSH
- protein C9orf72 genetika MeSH
- rodina MeSH
- rodokmen MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.
- MeSH
- alely MeSH
- Alzheimerova nemoc genetika MeSH
- celogenomová asociační studie metody MeSH
- dospělí MeSH
- expanze repetic DNA MeSH
- frontotemporální lobární degenerace * epidemiologie genetika MeSH
- haplotypy MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 9 genetika MeSH
- molekulární sekvence - údaje MeSH
- nestabilita genomu * MeSH
- prevalence MeSH
- protein C9orf72 MeSH
- proteiny * genetika MeSH
- sekvence nukleotidů MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Geografické názvy
- Evropa MeSH
- Finsko MeSH
- Německo MeSH
- Španělsko MeSH
- Švédsko MeSH
