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Article ; Online: Specific biomarkers for C9orf72 FTD/ALS could expedite the journey towards effective therapies

Rubika Balendra / Thomas G Moens / Adrian M Isaacs

EMBO Molecular Medicine, Vol 9, Iss 7, Pp 853-

2017 Volume 855

Abstract: A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The repeats are translated into five different dipeptide repeat proteins (DPRs). In this issue, Lehmer et al (2017) demonstrate that one of these DPRs, poly( ... ...

Abstract	A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The repeats are translated into five different dipeptide repeat proteins (DPRs). In this issue, Lehmer et al (2017) demonstrate that one of these DPRs, poly(GP), can be measured in the CSF of individuals with C9orf72 mutations. In conjunction with the findings from another recent study (Gendron et al, 2017), these DPR biomarkers may prove to be extremely valuable in the quest for effective therapies for C9FTD/ALS.
Keywords	Medicine (General) ; R5-920 ; Genetics ; QH426-470
Language	English
Publishing date	2017-07-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Quantitative analysis of cryptic splicing associated with TDP-43 depletion

Jack Humphrey / Warren Emmett / Pietro Fratta / Adrian M. Isaacs / Vincent Plagnol

BMC Medical Genomics, Vol 10, Iss 1, Pp 1-

2017 Volume 17

Abstract: Abstract Background Reliable exon recognition is key to the splicing of pre-mRNAs into mature mRNAs. TDP-43 is an RNA-binding protein whose nuclear loss and cytoplasmic aggregation are a hallmark pathology in amyotrophic lateral sclerosis and ... ...

Abstract	Abstract Background Reliable exon recognition is key to the splicing of pre-mRNAs into mature mRNAs. TDP-43 is an RNA-binding protein whose nuclear loss and cytoplasmic aggregation are a hallmark pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). TDP-43 depletion causes the aberrant inclusion of cryptic exons into a range of transcripts, but their extent, relevance to disease pathogenesis and whether they are caused by other RNA-binding proteins implicated in ALS/FTD are unknown. Methods We developed an analysis pipeline to discover and quantify cryptic exon inclusion and applied it to publicly available human and murine RNA-sequencing data. Results We detected widespread cryptic splicing in TDP-43 depletion datasets but almost none in another ALS/FTD-linked protein FUS. Sequence motif and iCLIP analysis of cryptic exons demonstrated that they are bound by TDP-43. Unlike the cryptic exons seen in hnRNP C depletion, those repressed by TDP-43 cannot be linked to transposable elements. Cryptic exons are poorly conserved and inclusion overwhelmingly leads to nonsense-mediated decay of the host transcript, with reduced transcript levels observed in differential expression analysis. RNA-protein interaction data on 73 different RNA-binding proteins showed that, in addition to TDP-43, 7 specifically bind TDP-43 linked cryptic exons. This suggests that TDP-43 competes with other splicing factors for binding to cryptic exons and can repress cryptic exon inclusion. Conclusions Our quantitative analysis pipeline confirms the presence of cryptic exons during the depletion of TDP-43 but not FUS providing new insight into to RNA-processing dysfunction as a cause or consequence in ALS/FTD.
Keywords	RNA-seq ; Cryptic exons ; Splicing ; TDP-43 ; Internal medicine ; RC31-1245 ; Genetics ; QH426-470
Language	English
Publishing date	2017-05-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9

Björn F. Vahsen / Sumedha Nalluru / Georgia R. Morgan / Lucy Farrimond / Emily Carroll / Yinyan Xu / Kaitlyn M. L. Cramb / Benazir Amein / Jakub Scaber / Antigoni Katsikoudi / Ana Candalija / Mireia Carcolé / Ruxandra Dafinca / Adrian M. Isaacs / Richard Wade-Martins / Elizabeth Gray / Martin R. Turner / Sally A. Cowley / Kevin Talbot

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 16

Abstract: Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic ... ...

Abstract	Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.
Keywords	Science ; Q
Language	English
Publishing date	2023-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

Magda L Atilano / Sebastian Grönke / Teresa Niccoli / Liam Kempthorne / Oliver Hahn / Javier Morón-Oset / Oliver Hendrich / Miranda Dyson / Mirjam Lisette Adams / Alexander Hull / Marie-Therese Salcher-Konrad / Amy Monaghan / Magda Bictash / Idoia Glaria / Adrian M Isaacs / Linda Partridge

eLife, Vol

2021 Volume 10

Abstract: G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat ... ...

Abstract	G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/IGF signalling is reduced in fly models of C9orf72 repeat expansion using RNA sequencing of adult brain. We further demonstrate that activation of insulin/IGF signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/IGF signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/IGF signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.
Keywords	hexanucleotide repeats ; C9orf72 ; insulin signalling ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: G-quadruplexes: Emerging roles in neurodegenerative diseases and the non-coding transcriptome

Simone, Roberto / Pietro Fratta / Stephen Neidle / Gary N. Parkinson / Adrian M. Isaacs

Federation of European Biochemical Societies FEBS letters. 2015 June 22, v. 589, no. 14

2015

Abstract: G-rich sequences in DNA and RNA have a propensity to fold into stable secondary structures termed G-quadruplexes. G-quadruplex forming sequences are widespread throughout the human genome, within both, protein coding and non-coding genes, and regulatory ... ...

Abstract	G-rich sequences in DNA and RNA have a propensity to fold into stable secondary structures termed G-quadruplexes. G-quadruplex forming sequences are widespread throughout the human genome, within both, protein coding and non-coding genes, and regulatory regions. G-quadruplexes have been implicated in multiple cellular functions including chromatin epigenetic regulation, DNA recombination, transcriptional regulation of gene promoters and enhancers, and translation. Here we will review the evidence for the occurrence of G-quadruplexes both in vitro and in vivo; their role in neurological diseases including G-quadruplex-forming repeat expansions in the C9orf72 gene in frontotemporal dementia and amyotrophic lateral sclerosis and loss of the G-quadruplex binding protein FMRP in the intellectual disability fragile X syndrome. We also review mounting evidence that supports a role for G-quadruplexes in regulating the processing or function of a range of non-coding RNAs. Finally we will highlight current perspectives for therapeutic interventions that target G-quadruplexes.
Keywords	DNA ; amyotrophic lateral sclerosis ; binding proteins ; chromatin ; dementia ; epigenetics ; genes ; humans ; non-coding RNA ; nucleotide sequences ; transcription (genetics) ; transcriptome ; translation (genetics)
Language	English
Dates of publication	2015-0622
Size	p. 1653-1668.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2015.05.003
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease [version 2; referees

Justin L. Tosh / Matthew Rickman / Ellie Rhymes / Frances E. Norona / Emma Clayton / Lennart Mucke / Adrian M. Isaacs / Elizabeth M.C. Fisher / Frances K. Wiseman

Wellcome Open Research, Vol

1 approved, 2 approved with reservations]

2018 Volume 2

Abstract: Background: Transgenic animal models are a widely used and powerful tool to investigate human disease and develop therapeutic interventions. Making a transgenic mouse involves random integration of exogenous DNA into the host genome that can have the ... ...

Abstract	Background: Transgenic animal models are a widely used and powerful tool to investigate human disease and develop therapeutic interventions. Making a transgenic mouse involves random integration of exogenous DNA into the host genome that can have the effect of disrupting endogenous gene expression. The J20 mouse model of Alzheimer’s disease (AD) is a transgenic overexpresser of human APP with familial AD mutations and has been extensively utilised in preclinical studies and our aim was to determine the genomic location of the J20 transgene insertion. Methods: We used a combination of breeding strategy and Targeted Locus Amplification with deep sequencing to identify the insertion site of the J20 transgene array. To assess RNA and protein expression of Zbtb20, we used qRT-PCR and Western Blotting. Results: We demonstrate that the J20 transgene construct has inserted within the genetic locus of endogenous mouse gene Zbtb20 on chromosome 16 in an array, disrupting expression of mRNA from this gene in adult hippocampal tissue. Preliminary data suggests that ZBTB20 protein levels remain unchanged in this tissue, however further study is necessary. We note that the endogenous mouse App gene also lies on chromosome 16, although 42 Mb from the Zbtb20 locus. Conclusions: These data will be useful for future studies utilising this popular model of AD, particularly those investigating gene interactions between the J20 APP transgene and other genes present on Mmu16 in the mouse.
Keywords	Animal Genetics ; Cognitive Neurology & Dementia ; Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	Wellcome
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The integration site of the APP transgene in the J20 mouse model of Alzheimer’s disease [version 1; referees

Justin L. Tosh / Matthew Rickman / Ellie Rhymes / Frances E. Norona / Emma Clayton / Lennart Mucke / Adrian M. Isaacs / Elizabeth M.C. Fisher / Frances K. Wiseman

Wellcome Open Research, Vol

1 approved, 2 approved with reservations]

2017 Volume 2

Abstract	Background: Transgenic animal models are a widely used and powerful tool to investigate human disease and develop therapeutic interventions. Making a transgenic mouse involves random integration of exogenous DNA into the host genome that can have the effect of disrupting endogenous gene expression. The J20 mouse model of Alzheimer’s disease (AD) is a transgenic overexpresser of human APP with familial AD mutations and has been extensively utilised in preclinical studies and our aim was to determine the genomic location of the J20 transgene insertion. Methods: We used a combination of breeding strategy and Targeted Locus Amplification with deep sequencing to identify the insertion site of the J20 transgene array. To assess RNA and protein expression of Zbtb20, we used qRT-PCR and Western Blotting. Results: We demonstrate that the J20 transgene construct has inserted within the genetic locus of endogenous mouse gene Zbtb20 on chromosome 16 in an array, disrupting expression of mRNA from this gene in adult hippocampal tissue, while expression of Zbtb20 protein remains unchanged. We note that the endogenous mouse App gene also lies on chromosome 16, although 42 Mb from the Zbtb20 locus. Conclusions: These data will be useful for future studies utilising this popular model of AD, particularly those investigating gene interactions between the J20 APP transgene and other genes present on Mmu16 in the mouse.
Keywords	Animal Genetics ; Cognitive Neurology & Dementia ; Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Wellcome
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Quantitative Assessment of Eye Phenotypes for Functional Genetic Studies Using Drosophila melanogaster

Janani Iyer / Qingyu Wang / Thanh Le / Lucilla Pizzo / Sebastian Grönke / Surendra S. Ambegaokar / Yuzuru Imai / Ashutosh Srivastava / Beatriz Llamusí Troisí / Graeme Mardon / Ruben Artero / George R. Jackson / Adrian M. Isaacs / Linda Partridge / Bingwei Lu / Justin P. Kumar / Santhosh Girirajan

G3 : Genes, Genomes, Genetics, Vol 6, Iss 5, Pp 1427-

2016 Volume 1437

Abstract: About two-thirds of the vital genes in the Drosophila genome are involved in eye development, making the fly eye an excellent genetic system to study cellular function and development, neurodevelopment/degeneration, and complex diseases such as cancer ... ...

Abstract	About two-thirds of the vital genes in the Drosophila genome are involved in eye development, making the fly eye an excellent genetic system to study cellular function and development, neurodevelopment/degeneration, and complex diseases such as cancer and diabetes. We developed a novel computational method, implemented as Flynotyper software (http://flynotyper.sourceforge.net), to quantitatively assess the morphological defects in the Drosophila eye resulting from genetic alterations affecting basic cellular and developmental processes. Flynotyper utilizes a series of image processing operations to automatically detect the fly eye and the individual ommatidium, and calculates a phenotypic score as a measure of the disorderliness of ommatidial arrangement in the fly eye. As a proof of principle, we tested our method by analyzing the defects due to eye-specific knockdown of Drosophila orthologs of 12 neurodevelopmental genes to accurately document differential sensitivities of these genes to dosage alteration. We also evaluated eye images from six independent studies assessing the effect of overexpression of repeats, candidates from peptide library screens, and modifiers of neurotoxicity and developmental processes on eye morphology, and show strong concordance with the original assessment. We further demonstrate the utility of this method by analyzing 16 modifiers of sine oculis obtained from two genome-wide deficiency screens of Drosophila and accurately quantifying the effect of its enhancers and suppressors during eye development. Our method will complement existing assays for eye phenotypes, and increase the accuracy of studies that use fly eyes for functional evaluation of genes and genetic interactions.
Keywords	ommatidia ; Drosophila melanogaster ; neurodevelopmental disorders ; modifier screens ; rough eye ; human disease models ; Genetics ; QH426-470 ; Biology (General) ; QH301-705.5 ; Science ; Q
Subject code	590
Language	English
Publishing date	2016-05-01T00:00:00Z
Publisher	Genetics Society of America
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: G‐quadruplex‐binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo

Roberto Simone / Rubika Balendra / Thomas G Moens / Elisavet Preza / Katherine M Wilson / Amanda Heslegrave / Nathan S Woodling / Teresa Niccoli / Javier Gilbert‐Jaramillo / Samir Abdelkarim / Emma L Clayton / Mica Clarke / Marie‐Therese Konrad / Andrew J Nicoll / Jamie S Mitchell / Andrea Calvo / Adriano Chio / Henry Houlden / James M Polke /

Mohamed A Ismail / Chad E Stephens / Tam Vo / Abdelbasset A Farahat / W David Wilson / David W Boykin / Henrik Zetterberg / Linda Partridge / Selina Wray / Gary Parkinson / Stephen Neidle / Rickie Patani / Pietro Fratta / Adrian M Isaacs

EMBO Molecular Medicine, Vol 10, Iss 1, Pp 22-

2018 Volume 31

Abstract: Abstract Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat ... ...

Abstract	Abstract Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA‐binding proteins and through toxic dipeptide repeat proteins generated by repeat‐associated non‐ATG translation. GGGGCC repeat RNA folds into a G‐quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G‐quadruplex RNA. We investigated their effect in C9orf72 patient iPSC‐derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat‐expressing Drosophila. Therefore, small molecules that target GGGGCC repeat G‐quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS. These data provide proof of principle that targeting GGGGCC repeat G‐quadruplexes has therapeutic potential.
Keywords	amyotrophic lateral sclerosis ; C9orf72 ; frontotemporal dementia ; G‐quadruplex ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	571
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits

Guillaume M. Hautbergue / Lydia M. Castelli / Laura Ferraiuolo / Alvaro Sanchez-Martinez / Johnathan Cooper-Knock / Adrian Higginbottom / Ya-Hui Lin / Claudia S. Bauer / Jennifer E. Dodd / Monika A. Myszczynska / Sarah M. Alam / Pierre Garneret / Jayanth S. Chandran / Evangelia Karyka / Matthew J. Stopford / Emma F. Smith / Janine Kirby / Kathrin Meyer / Brian K. Kaspar /

Adrian M. Isaacs / Sherif F. El-Khamisy / Kurt J. De Vos / Ke Ning / Mimoun Azzouz / Alexander J. Whitworth / Pamela J. Shaw

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 18

Abstract: The RNA for ALS- and frontotemporal dementia-associated C9ORF72 gene is exported from nucleus via an unknown mechanism. This study shows that reduction of nuclear export adaptor SRSF1 can alleviate neuronal cell death and nuclear export of C9ORF72 ... ...

Abstract	The RNA for ALS- and frontotemporal dementia-associated C9ORF72 gene is exported from nucleus via an unknown mechanism. This study shows that reduction of nuclear export adaptor SRSF1 can alleviate neuronal cell death and nuclear export of C9ORF72 inDrosophilaand patient-derived induced motor neurons.
Keywords	Science ; Q
Language	English
Publishing date	2017-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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