Early life involvement in C9orf72 repeat expansion carriers

ObjectivesThe chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72RE-associated disease is sometimes hard to define, we hypothesise that C9orf72RE may cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72RE. Second, we aimed to describe distinctive characteristics of C9orf72RE during disease course.MethodsOut of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72RE bvFTD patients and 23 C9orf72RE negative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses.ResultsEducation, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having ‘fixed behavioural patterns in daily life’ and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers.ConclusionThis is the first study thoroughly exploring biographies of bvFTD patients with C9orf72RE, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72RE exerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72RE -associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.

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Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD

Emerging Topics in Life Sciences ◽

10.1042/etls20190167 ◽

2020 ◽

Vol 4 (3) ◽

pp. 293-305

Author(s):

Hana M. Odeh ◽

James Shorter

Keyword(s):

Rna Binding ◽

Rna Binding Proteins ◽

Low Complexity ◽

Repeat Expansion ◽

Chromosome 9 ◽

Reading Frame ◽

Hexanucleotide Repeat ◽

Hexanucleotide Repeat Expansion ◽

Lateral Sclerosis ◽

Dipeptide Repeat

A hexanucleotide repeat expansion GGGGCC (G4C2) within chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). This seminal realization has rapidly focused our attention to the non-canonical translation (RAN translation) of the repeat expansion, which yields dipeptide-repeat protein products (DPRs). The mechanisms by which DPRs might contribute to C9-ALS/FTD are widely studied. Arginine-rich DPRs (R-DPRs) are the most toxic of the five different DPRs produced in neurons, but how do R-DPRs promote C9-ALS/FTD pathogenesis? Proteomic analyses have uncovered potential pathways to explore. For example, the vast majority of the R-DPR interactome is comprised of disease-linked RNA-binding proteins (RBPs) with low-complexity domains (LCDs), strongly suggesting a link between R-DPRs and aberrations in liquid–liquid phase separation (LLPS). In this review, we showcase several potential mechanisms by which R-DPRs disrupt various phase-separated compartments to elicit deleterious neurodegeneration. We also discuss potential therapeutic strategies to counter R-DPR toxicity in C9-ALS/FTD.

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The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms19103137 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3137 ◽

Cited By ~ 12

Author(s):

Anna Konopka ◽

Julie Atkin

Keyword(s):

Dna Damage ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Repeat Expansion ◽

Chromosome 9 ◽

Gene Encoding ◽

C9orf72 Repeat Expansion ◽

Reading Frame ◽

Early Onset Dementia ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.

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Screening for C9orf72 Expansion Mutation in Serbian Patients with Early-Onset Dementia

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000438748 ◽

2015 ◽

Vol 40 (5-6) ◽

pp. 358-365 ◽

Cited By ~ 2

Author(s):

Gorana Mandic-Stojmenovic ◽

Elka Stefanova ◽

Valerija Dobricic ◽

Ivana Novakovic ◽

Tanja Stojkovic ◽

...

Keyword(s):

Early Onset ◽

Lewy Bodies ◽

Chromosome 9 ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Reading Frame ◽

Early Onset Dementia ◽

Hexanucleotide Repeat ◽

Disease Spectrum ◽

Hexanucleotide Repeat Expansion ◽

Expansion Mutation

Background: Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia (EOD), characterized by behavioral changes (behavioral variant; bvFTD) or language deficits. A hexanucleotide repeat expansion in a noncoding region of chromosome 9 open reading frame 72 (C9orf72) has been proved to be a major cause of both familial and sporadic amyotrophic lateral sclerosis or FTD, with or without concomitant motor neuron disease (MND). Methods: The aim of this study was to assess the frequency of the C9orf72 hexanucleotide expansion in a cohort of 117 Serbian patients with EOD and to report phenotypic features of identified carriers. Results: We identified 4 of 117 (3.4%) patients with EOD to have C9orf72 hexanucleotide expansions. All patients were classified in the FTD disease spectrum group (8.2%): 3 patients fulfilled the criteria for bvFTD, and 1 patient had FTD-MND. None of the patients with the C9orf72 hexanucleotide expansion fulfilled the diagnostic criteria for language variants of FTD, FTD-progressive supranuclear palsy overlap syndrome, dementia with Lewy bodies or Alzheimer's dementia. Conclusion: In a cohort of consecutive patients with EOD, 3.4% had the C9orf72 hexanucleotide expansion with clinical phenotypes of bvFTD or an overlap of bvFTD and MND.

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Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion

Behavioural Neurology ◽

10.1155/2019/2909168 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 18

Author(s):

Mirjana Babić Leko ◽

Vera Župunski ◽

Jason Kirincich ◽

Dinko Smilović ◽

Tibor Hortobágyi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Phase 1 ◽

Nucleocytoplasmic Transport ◽

Normal Function ◽

Repeat Expansion ◽

Chromosome 9 ◽

Gain Of Function ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Hexanucleotide Repeat Expansion

Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2–10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.

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A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy

Science Advances ◽

10.1126/sciadv.1601167 ◽

2016 ◽

Vol 2 (9) ◽

pp. e1601167 ◽

Cited By ~ 114

Author(s):

Mei Yang ◽

Chen Liang ◽

Kunchithapadam Swaminathan ◽

Stephanie Herrlinger ◽

Fan Lai ◽

...

Keyword(s):

Chromosome 9 ◽

Autophagic Flux ◽

Reading Frame ◽

Guanosine Diphosphate ◽

Hexanucleotide Repeat ◽

Autophagy Induction ◽

Important Regulator ◽

Hexanucleotide Repeat Expansion ◽

Guanosine Triphosphatase ◽

Mutant Cells

The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate–guanosine 5′-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B. We created Smcr8 knockout mice and found that Smcr8 mutant cells exhibit impaired autophagy induction, which is similarly observed in C9orf72 knockdown cells. Mechanistically, SMCR8/C9ORF72 interacts with the key autophagy initiation ULK1 complex and regulates expression and activity of ULK1. The complex has an additional role in regulating later stages of autophagy. Whereas autophagic flux is enhanced in C9orf72 knockdown cells, depletion of Smcr8 results in a reduced flux with an abnormal expression of lysosomal enzymes. Thus, C9ORF72 and SMCR8 have similar functions in modulating autophagy induction by regulating ULK1 and play distinct roles in regulating autophagic flux.

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Novel Evidence of Phenotypical Variability in the Hexanucleotide Repeat Expansion in Chromosome 9

Journal of Alzheimer s Disease ◽

10.3233/jad-122302 ◽

2013 ◽

Vol 35 (3) ◽

pp. 455-462 ◽

Cited By ~ 10

Author(s):

Chiara Cerami ◽

Alessandra Marcone ◽

Daniela Galimberti ◽

Michele Zamboni ◽

Chiara Fenoglio ◽

...

Keyword(s):

Repeat Expansion ◽

Chromosome 9 ◽

Hexanucleotide Repeat ◽

Hexanucleotide Repeat Expansion ◽

Phenotypical Variability

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Faculty Opinions recommendation of A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13294966.14655067 ◽

2011 ◽

Author(s):

Martin Rossor ◽

Jonathan Rohrer

Keyword(s):

Repeat Expansion ◽

Chromosome 9P21 ◽

Hexanucleotide Repeat ◽

Hexanucleotide Repeat Expansion

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C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Science Advances ◽

10.1126/sciadv.abg3013 ◽

2021 ◽

Vol 7 (15) ◽

pp. eabg3013

Author(s):

Laura Fumagalli ◽

Florence L. Young ◽

Steven Boeynaems ◽

Mathias De Decker ◽

Arpan R. Mehta ◽

...

Keyword(s):

Axonal Transport ◽

Motor Neurons ◽

Single Molecule ◽

Repeat Expansion ◽

Physical Interaction ◽

Hexanucleotide Repeat ◽

Hexanucleotide Repeat Expansion ◽

Axonal Trafficking ◽

Inhibitory Interactions

A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we show using patient stem cell–derived motor neurons that the repeat expansion impairs microtubule-based transport, a process critical for neuronal survival. Cargo transport defects are recapitulated by treating neurons from healthy individuals with proline-arginine and glycine-arginine dipeptide repeats (DPRs) produced from the repeat expansion. Both arginine-rich DPRs similarly inhibit axonal trafficking in adult Drosophila neurons in vivo. Physical interaction studies demonstrate that arginine-rich DPRs associate with motor complexes and the unstructured tubulin tails of microtubules. Single-molecule imaging reveals that microtubule-bound arginine-rich DPRs directly impede translocation of purified dynein and kinesin-1 motor complexes. Collectively, our study implicates inhibitory interactions of arginine-rich DPRs with axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to potential therapeutic strategies.

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