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

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.

scholarly journals Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Magda L Atilano ◽  
Sebastian Grönke ◽  
Teresa Niccoli ◽  
Liam Kempthorne ◽  
Oliver Hahn ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Insulin Signalling ◽  
Repeat Expansion ◽  
Adult Brain ◽  
Systemic Injection ◽  
Hexanucleotide Repeat ◽  
Repeat Expansions ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

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.

scholarly journals C9-ALS/FTD-linked proline–arginine dipeptide repeat protein associates with paraspeckle components and increases paraspeckle formation

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Hiroaki Suzuki ◽  
Yoshio Shibagaki ◽  
Seisuke Hattori ◽  
Masaaki Matsuoka
Keyword(s):  
Dna Binding Protein ◽  
Repeat Expansion ◽  
Hexanucleotide Repeat ◽  
Repeat Proteins ◽  
Non Coding Rna ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

Abstract A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene has been identified as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeat expansion undergoes unconventional translation to produce five dipeptide repeat proteins (DPRs). Although DPRs are thought to be neurotoxic, the molecular mechanism underlying the DPR-caused neurotoxicity has not been fully elucidated. The current study shows that poly-proline-arginine (poly-PR), the most toxic DPR in vitro, binds to and up-regulates nuclear paraspeckle assembly transcript 1 (NEAT1) that plays an essential role as a scaffold non-coding RNA during the paraspeckle formation. The CRISPR-assisted up-regulation of endogenous NEAT1 causes neurotoxicity. We also show that the poly-PR modulates the function of several paraspeckle-localizing heterogeneous nuclear ribonucleoproteins. Furthermore, dysregulated expression of TAR DNA-binding protein 43 (TDP-43) up-regulates NEAT1 expression and induces neurotoxicity. These results suggest that the increase in the paraspeckle formation may be involved in the poly-PR- and TDP-43-mediated neurotoxicity.

scholarly journals HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS

2022 ◽  
Vol 9 ◽  
Author(s):  
Giulia del Rosso ◽  
Yari Carlomagno ◽  
Tiffany W. Todd ◽  
Caroline Y. Jones ◽  
Mercedes Prudencio ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Cultured Cells ◽  
Repeat Expansion ◽  
Chromosome 9 ◽  
Physical Interaction ◽  
Reading Frame ◽  
Therapeutic Value ◽  
The Central Nervous System ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results in the accumulation of toxic dipeptide repeat (DPR) proteins in the central nervous system We have found that, among the sense DPR proteins, HDAC6 specifically interacts with the poly (GA) and co-localizes with inclusions in both patient tissue and a mouse model of this disease (c9FTD/ALS). Overexpression of HDAC6 increased poly (GA) levels in cultured cells independently of HDAC6 deacetylase activity, suggesting that HDAC6 can modulate poly (GA) pathology through a mechanism that depends upon their physical interaction. Moreover, decreasing HDAC6 expression by stereotaxic injection of antisense oligonucleotides significantly reduced the number of poly (GA) inclusions in c9FTD/ALS mice. These findings suggest that pharmacologically reducing HDAC6 levels could be of therapeutic value in c9FTD/ALS.

scholarly journals Circadian sleep/wake-associated cells show dipeptide repeat protein aggregates in C9orf72-related ALS and FTLD cases

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Lieselot Dedeene ◽  
Evelien Van Schoor ◽  
Rik Vandenberghe ◽  
Philip Van Damme ◽  
Koen Poesen ◽  
...  
Keyword(s):  
Frontotemporal Lobar Degeneration ◽  
Sleep Disturbances ◽  
Motor Behavior ◽  
Repeat Expansion ◽  
Repeat Protein ◽  
Hexanucleotide Repeat ◽  
Gland Tissue ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractMotor-, behavior- and/or cognition-related symptoms are key hallmarks in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLD-TDP), respectively. It has been reported that these patients also experience sleep disturbances, which might implicate a disturbed circadian rhythm of the sleep/wake cycle. It remains unknown, however, whether cells involved in the circadian sleep/wake cycle are affected by ALS- and FTLD-related neuropathological changes including phosphorylated TDP-43 (pTDP-43) aggregates and dipeptide repeat protein (DPR) inclusions resulting from the C9orf72 hexanucleotide repeat expansion. Immunohistochemistry for DPR and pTDP-43 pathology was performed in post-mortem hypothalamus and pineal gland tissue of patients with ALS and/or FTLD-TDP with and without the C9orf72 repeat expansion and healthy controls. Circadian sleep/wake-associated cells, including pinealocytes and hypothalamic neurons related to the suprachiasmatic nucleus (SCN), were microscopically assessed. We observed numerous DPR inclusions (poly(GA), poly(GP), poly(GR) and poly(PR)) in the pinealocytes and few poly(GA) inclusions in the SCN-related neurons in C9orf72-related ALS and/or FTLD-TDP cases. These circadian sleep/wake-associated cells, however, were devoid of pTDP-43 pathology both in C9orf72- and nonC9orf72-related ALS and/or FTLD-TDP cases. Our neuropathological findings show that pinealocytes and, to a lesser extent, SCN-related neurons are affected by DPR pathology. This may reflect an involvement of these cells in sleep/wake disturbances observed in ALS and/or FTLD-TDP patients.

Early life involvement in C9orf72 repeat expansion carriers

2021 ◽  
pp. jnnp-2020-325994
Author(s):  
Flora Gossink ◽  
Annemiek Dols ◽  
Max L Stek ◽  
Philip Scheltens ◽  
Bas Nijmeijer ◽  
...  
Keyword(s):  
Repeat Expansion ◽  
Chromosome 9 ◽  
Disease Course ◽  
C9orf72 Repeat Expansion ◽  
Reading Frame ◽  
Professional Career ◽  
Hexanucleotide Repeat ◽  
Behavioural Patterns ◽  
Quantitative Analyses ◽  
Hexanucleotide Repeat Expansion

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.

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

2018 ◽  
Vol 19 (10) ◽  
pp. 3137 ◽  
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.

scholarly journals RNA-binding proteins with prion-like domains in health and disease

2017 ◽  
Vol 474 (8) ◽  
pp. 1417-1438 ◽  
Author(s):  
Alice Ford Harrison ◽  
James Shorter
Keyword(s):  
Phase Transitions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Low Complexity ◽  
Fused In Sarcoma ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Health And Disease ◽  
Lateral Sclerosis

Approximately 70 human RNA-binding proteins (RBPs) contain a prion-like domain (PrLD). PrLDs are low-complexity domains that possess a similar amino acid composition to prion domains in yeast, which enable several proteins, including Sup35 and Rnq1, to form infectious conformers, termed prions. In humans, PrLDs contribute to RBP function and enable RBPs to undergo liquid–liquid phase transitions that underlie the biogenesis of various membraneless organelles. However, this activity appears to render RBPs prone to misfolding and aggregation connected to neurodegenerative disease. Indeed, numerous RBPs with PrLDs, including TDP-43 (transactivation response element DNA-binding protein 43), FUS (fused in sarcoma), TAF15 (TATA-binding protein-associated factor 15), EWSR1 (Ewing sarcoma breakpoint region 1), and heterogeneous nuclear ribonucleoproteins A1 and A2 (hnRNPA1 and hnRNPA2), have now been connected via pathology and genetics to the etiology of several neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Here, we review the physiological and pathological roles of the most prominent RBPs with PrLDs. We also highlight the potential of protein disaggregases, including Hsp104, as a therapeutic strategy to combat the aberrant phase transitions of RBPs with PrLDs that likely underpin neurodegeneration.

scholarly journals C9orf72 Hexanucleotide Repeat Expansion and Guam Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex

2013 ◽  
Vol 70 (6) ◽  
pp. 742 ◽  
Author(s):  
Beth A. Dombroski ◽  
Douglas R. Galasko ◽  
Ignacio F. Mata ◽  
Cyrus P. Zabetian ◽  
Ulla-Katrina Craig ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Repeat Expansion ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis
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