Erratum to: Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing

Schludi, Martin H.; May, Stephanie; Grässer, Friedrich A.; Rentzsch, Kristin; Kremmer, Elisabeth; Küpper, Clemens; Klopstock, Thomas; Arzberger, Thomas; Edbauer, Dieter

doi:10.1007/s00401-015-1464-6

Cited by 3 publications

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“…PR was observed to be nuclear and cytoplasmic in both ex vivo Drosophila brains and primary neurons. These results are comparable to those observed previously is SH-SY5Y cells and patient tissue [2,28]. GR showed nuclear and cytoplasmic localisation similar to that observed in post-mortem patient tissue [28].…”

Section: Dprs Show Distinct Localisation Patterns Within the Drosophisupporting

confidence: 91%

Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

West

Sharpe

Voelzmann

et al. 2020

acta neuropathol commun

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A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs effect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profile. Furthermore, we show co-expression of specific DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD.

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Section: Dprs Show Distinct Localisation Patterns Within the Drosophisupporting

confidence: 91%

Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

West

Sharpe

Voelzmann

et al. 2020

acta neuropathol commun

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“…Several studies, including our own, show that hypermethylation of the CpG-island at the 5′ end of the repeat contributes to C9orf72 repression in a high of C9orf72 -HRE carriers, yet down-regulation of C9orf72 is more prevalent and shown among FTD sporadic patients [ 19 ] and MAPT and GRN mutation carriers (this study). Very recently, co-localization of para-nucleolar DPR proteins inclusions with heterochomatin and H3K9me2 [ 18 ], a marker of transcriptional repression linked to R-loop-induced transcriptional silencing, has been reported [ 62 ]. In light of these findings it would be interesting to determine whether and to what extent the C9orf72 antisense AS3 affects histone modifications at the C9orf72 locus not only in C9orf72 -HRE but also in MAPT and GRN patients.…”

Section: Discussionmentioning

confidence: 99%

“…The C9orf72 DPR proteins accumulate into cytoplasmic and intranuclear inclusions in brains of patients [ 12 – 16 ]. And studies in cell culture and animal models strongly corroborate that overexpression of DPR proteins is toxic and can induce nuclear inclusions and nucleolar stress [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers

Rizzu

Blauwendraat

Heetveld

et al. 2016

acta neuropathol commun

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A non-coding hexanucleotide repeat expansion (HRE) in C9orf72 is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) acting through a loss of function mechanism due to haploinsufficiency of C9orf72 or a gain of function mediated by aggregates of bidirectionally transcribed HRE-RNAs translated into di-peptide repeat (DPR) proteins. To fully understand regulation of C9orf72 expression we surveyed the C9orf72 locus using Cap Analysis of Gene Expression sequence data (CAGEseq). We observed C9orf72 was generally lowly expressed with the exception of a subset of myeloid cells, particularly CD14+ monocytes that showed up to seven fold higher expression as compared to central nervous system (CNS) and other tissues. The expression profile at the C9orf72 locus showed a complex architecture with differential expression of the transcription start sites (TSSs) for the annotated C9orf72 transcripts between myeloid and CNS tissues suggesting cell and/or tissue specific functions. We further detected novel TSSs in both the sense and antisense strand at the C9orf72 locus and confirmed their existence in brain tissues and CD14+ monocytes. Interestingly, our experiments showed a consistent decrease of C9orf72 coding transcripts not only in brain tissue and monocytes from C9orf72-HRE patients, but also in brains from MAPT and GRN mutation carriers together with an increase in antisense transcripts suggesting these could play a role in regulation of C9orf72. We found that the non-HRE related expression changes cannot be explained by promoter methylation but by the presence of the C9orf72-HRE risk haplotype and unknown functional interactions between C9orf72, MAPT and GRN.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0306-7) contains supplementary material, which is available to authorized users.

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“…The main argument against the role of DPRs as a main driver of toxicity comes from neuropathological analysis using human brain tissue, which has revealed that DPR distribution is not spatially correlated to severity of degeneration in ALS or FTD (Mackenzie et al, 2013; Davidson et al, 2014, 2016; Gomez-Deza et al, 2015; Schuldi et al, 2015). In fact, DPR load is lower in vulnerable regions (e.g., motor cortex) and higher in unaffected areas (e.g., cerebellum) (Mackenzie et al, 2013), suggestive of a possible neuroprotective role for insoluble DPR aggregates.…”

Section: Assessing the Relative Contribution Of Rna Foci And Dpr Accumentioning

confidence: 99%

RNA Misprocessing in C9orf72-Linked Neurodegeneration

Barker

Niblock

Lee

et al. 2017

Front. Cell. Neurosci.

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A large GGGGCC hexanucleotide repeat expansion in the first intron or promoter region of the C9orf72 gene is the most common genetic cause of familial and sporadic Amyotrophic lateral sclerosis (ALS), a devastating degenerative disease of motor neurons, and of Frontotemporal Dementia (FTD), the second most common form of presenile dementia after Alzheimer’s disease. C9orf72-associated ALS/FTD is a multifaceted disease both in terms of its clinical presentation and the misregulated cellular pathways contributing to disease progression. Among the numerous pathways misregulated in C9orf72-associated ALS/FTD, altered RNA processing has consistently appeared at the forefront of C9orf72 research. This includes bidirectional transcription of the repeat sequence, accumulation of repeat RNA into nuclear foci sequestering specific RNA-binding proteins (RBPs) and translation of RNA repeats into dipeptide repeat proteins (DPRs) by repeat-associated non-AUG (RAN)-initiated translation. Over the past few years the true extent of RNA misprocessing in C9orf72-associated ALS/FTD has begun to emerge and disruptions have been identified in almost all aspects of the life of an RNA molecule, including release from RNA polymerase II, translation in the cytoplasm and degradation. Furthermore, several alterations have been identified in the processing of the C9orf72 RNA itself, in terms of its transcription, splicing and localization. This review article aims to consolidate our current knowledge on the consequence of the C9orf72 repeat expansion on RNA processing and draws attention to the mechanisms by which several aspects of C9orf72 molecular pathology converge to perturb every stage of RNA metabolism.

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Erratum to: Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing

Abstract: As a result of an error during digital processing of Figure 1a for publication, one of the immunofluorescence panels (GA 175 -GFP Nucleolin staining) was accidentally strongly altered in contrast and brightness. The corrected version of the figure is shown below.

Cited by 3 publications

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Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers

RNA Misprocessing in C9orf72-Linked Neurodegeneration

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