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 Why TDP-43? Why Not? Mechanisms of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 15 ◽  
pp. 263310552095730 ◽  
Author(s):  
Mara-Luciana Floare ◽  
Scott P. Allen
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Chromosome 9 ◽  
Metabolic Dysfunction ◽  
Superoxide Dismutase 1 ◽  
Gene Encoding ◽  
Reading Frame ◽  
Fused In Sarcoma ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder for which there is no effective curative treatment available and minimal palliative care. Mutations in the gene encoding the TAR DNA-binding protein 43 (TDP-43) are a well-recognized genetic cause of ALS, and an imbalance in energy homeostasis correlates closely to disease susceptibility and progression. Considering previous research supporting a plethora of downstream cellular impairments originating in the histopathological signature of TDP-43, and the solid evidence around metabolic dysfunction in ALS, a causal association between TDP-43 pathology and metabolic dysfunction cannot be ruled out. Here we discuss how TDP-43 contributes on a molecular level to these impairments in energy homeostasis, and whether the protein’s pathological effects on cellular metabolism differ from those of other genetic risk factors associated with ALS such as superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72) and fused in sarcoma (FUS).

scholarly journals The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis

2017 ◽  
Vol 26 (15) ◽  
pp. 2882-2896 ◽  
Author(s):  
Manal A. Farg ◽  
Anna Konopka ◽  
Kai Ying Soo ◽  
Daisuke Ito ◽  
Julie D. Atkin
Keyword(s):  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Dna Damage Response ◽  
Repeat Expansion ◽  
C9orf72 Repeat Expansion ◽  
Damage Response ◽  
Lateral Sclerosis

scholarly journals Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Atsuhiko Sugiyama ◽  
Takahiro Takeda ◽  
Mizuho Koide ◽  
Hajime Yokota ◽  
Hiroki Mukai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Repeat Expansion ◽  
Cerebellar Hemisphere ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Lateral Sclerosis

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. Case presentation A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. Conclusions We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

scholarly journals C9ORF72 Repeat Expansion Affects the Proteome of Primary Skin Fibroblasts in ALS

2021 ◽  
Vol 22 (19) ◽  
pp. 10385
Author(s):  
Marta Lualdi ◽  
Adeena Shafique ◽  
Edoardo Pedrini ◽  
Luisa Pieroni ◽  
Viviana Greco ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Repeat Expansion ◽  
Skin Fibroblasts ◽  
Chromosome 9 ◽  
Functional Enrichment ◽  
Molecular Pathways ◽  
C9orf72 Repeat Expansion ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.

scholarly journals C9ORF72 Repeat Expansion in Amyotrophic Lateral Sclerosis in the Kii Peninsula of Japan

2012 ◽  
Vol 69 (9) ◽  
Author(s):  
Hiroyuki Ishiura ◽  
Yuji Takahashi ◽  
Jun Mitsui ◽  
Sohei Yoshida ◽  
Tameko Kihira ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Repeat Expansion ◽  
Kii Peninsula ◽  
C9orf72 Repeat Expansion ◽  
Lateral Sclerosis

scholarly journals Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 8 (5) ◽  
pp. 729 ◽  
Author(s):  
Matteo Bordoni ◽  
Orietta Pansarasa ◽  
Michela Dell’Orco ◽  
Valeria Crippa ◽  
Stella Gagliardi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Oxidative Damage ◽  
Motor Neurons ◽  
Mononuclear Cells ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Peripheral Blood Mononuclear ◽  
High Level ◽  
Lateral Sclerosis

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its consequent aggregation. We found an increase in DNA damage in patients PBMCs characterized by a high level of aggregated SOD1, while we found no DNA damage in PBMCs with normal soluble SOD1. We found an activation of ataxia-telangiectasia-mutated (ATM)/Chk2 and ATM and Rad3-related (ATR)/Chk1 DNA damage response pathways, which lead to phosphorylation of SOD1. Moreover, data showed that phosphorylation allows SOD1 to shift from the cytoplasm to the nucleus, protecting DNA from oxidative damage. Such pathway was finally confirmed in our cellular model. Our data lead us to suppose that in a sub-group of patients this physiologic pathway is non-functional, leading to an accumulation of DNA damage that causes the death of particularly susceptible cells, like motor neurons. In conclusion, during oxidative stress SOD1 is phosphorylated by Chk2 leading to its translocation in the nuclear compartment, in which SOD1 protects DNA from oxidative damage. This pathway, inefficient in sALS patients, could represent an innovative therapeutic target.

Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis

2012 ◽  
Vol 33 (10) ◽  
pp. 2527.e11-2527.e16 ◽  
Author(s):  
Kotaro Ogaki ◽  
Yuanzhe Li ◽  
Naoki Atsuta ◽  
Hiroyuki Tomiyama ◽  
Manabu Funayama ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Japanese Patients ◽  
Repeat Expansion ◽  
C9orf72 Repeat Expansion ◽  
Lateral Sclerosis

scholarly journals Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

2021 ◽  
Vol 15 ◽  
Author(s):  
Iris-Stefania Pasniceanu ◽  
Manpreet Singh Atwal ◽  
Cleide Dos Santos Souza ◽  
Laura Ferraiuolo ◽  
Matthew R. Livesey
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Repeat Expansion ◽  
Neuronal Function ◽  
Repeat Expansion Mutation ◽  
Expansion Mutation ◽  
The Impact ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

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