scholarly journals The role of DNA damage response in amyotrophic lateral sclerosis

2020 ◽  
Vol 64 (5) ◽  
pp. 847-861 ◽  
Author(s):  
Yu Sun ◽  
Annabel J. Curle ◽  
Arshad M. Haider ◽  
Gabriel Balmus
Keyword(s):  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Genomic Instability ◽  
Dna Damage Response ◽  
Disease Mechanisms ◽  
Age Related ◽  
Sporadic Als ◽  
Damage Response ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a rapidly disabling and fatal neurodegenerative disease. Due to insufficient disease-modifying treatments, there is an unmet and urgent need for elucidating disease mechanisms that occur early and represent common triggers in both familial and sporadic ALS. Emerging evidence suggests that impaired DNA damage response contributes to age-related somatic accumulation of genomic instability and can trigger or accelerate ALS pathological manifestations. In this review, we summarize and discuss recent studies indicating a direct link between DNA damage response and ALS. Further mechanistic understanding of the role genomic instability is playing in ALS disease pathophysiology will be critical for discovering new therapeutic avenues.

scholarly journals RT2 PCR array screening reveals distinct perturbations in DNA damage response signaling in FUS-associated motor neuron disease

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Haibo Wang ◽  
Suganya Rangaswamy ◽  
Manohar Kodavati ◽  
Joy Mitra ◽  
Wenting Guo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Dna Damage Response ◽  
Spinal Cord Tissue ◽  
Sporadic Als ◽  
Damage Response ◽  
Als Patients

AbstractAmyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that has been linked to defective DNA repair. Many familial ALS patients harbor autosomal dominant mutations in the gene encoding the RNA/DNA binding protein ‘fused in sarcoma’ (FUS) commonly inducing its cytoplasmic mislocalization. Recent reports from our group and others demonstrate a role of FUS in maintaining genome integrity and the DNA damage response (DDR). FUS interacts with many DDR proteins and may regulate their recruitment at damage sites. Given the role of FUS in RNA transactions, here we explore whether FUS also regulates the expression of DDR factors. We performed RT2 PCR arrays for DNA repair and DDR signaling pathways in CRISPR/Cas9 FUS knockout (KO) and shRNA mediated FUS knockdown (KD) cells, which revealed significant (> 2-fold) downregulation of BRCA1, DNA ligase 4, MSH complex and RAD23B. Importantly, similar perturbations in these factors were also consistent in motor neurons differentiated from an ALS patient-derived induced pluripotent stem cell (iPSC) line with a FUS-P525L mutation, as well as in postmortem spinal cord tissue of sporadic ALS patients with FUS pathology. BRCA1 depletion has been linked to neuronal DNA double-strand breaks (DSBs) accumulation and cognitive defects. The ubiquitin receptor RAD23 functions both in nucleotide excision repair and proteasomal protein clearance pathway and is thus linked to neurodegeneration. Together, our study suggests that the FUS pathology perturbs DDR signaling via both its direct role and the effect on the expression of DDR genes. This underscors an intricate connections between FUS, genome instability, and neurodegeneration.

scholarly journals A Commentary on TDP-43 and DNA Damage Response in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 13 ◽  
pp. 117906951988016 ◽  
Author(s):  
Joy Mitra ◽  
Muralidhar L Hegde
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Amyotrophic Lateral Sclerosis ◽  
Dna Damage Response ◽  
Motor Neurons ◽  
Dsb Repair ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Damage Response ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating, motor neuron degenerative disease without any cure. About 95% of the ALS patients feature abnormalities in the RNA/DNA-binding protein, TDP-43, involving its nucleo-cytoplasmic mislocalization in spinal motor neurons. How TDP-43 pathology triggers neuronal apoptosis remains unclear. In a recent study, we reported for the first time that TDP-43 participates in the DNA damage response (DDR) in neurons, and its nuclear clearance in spinal motor neurons caused DNA double-strand break (DSB) repair defects in ALS. We documented that TDP-43 was a key component of the non-homologous end joining (NHEJ) pathway of DSB repair, which is likely the major pathway for repair of DSBs in post-mitotic neurons. We have also uncovered molecular insights into the role of TDP-43 in DSB repair and showed that TDP-43 acts as a scaffold in recruiting the XRCC4/DNA Ligase 4 complex at DSB damage sites and thus regulates a critical rate-limiting function in DSB repair. Significant DSB accumulation in the genomes of TDP-43-depleted, human neural stem cell-derived motor neurons as well as in ALS patient spinal cords with TDP-43 pathology, strongly supported a TDP-43 involvement in genome maintenance and toxicity-induced genome repair defects in ALS. In this commentary, we highlight our findings that have uncovered a link between TDP-43 pathology and impaired DNA repair and suggest potential possibilities for DNA repair-targeted therapies for TDP-43-ALS.

scholarly journals G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

2018 ◽  
Vol 19 (10) ◽  
pp. 2919 ◽  
Author(s):  
Hanne Leysen ◽  
Jaana van Gastel ◽  
Jhana Hendrickx ◽  
Paula Santos-Otte ◽  
Bronwen Martin ◽  
...  
Keyword(s):  
Dna Damage ◽  
G Protein ◽  
Dna Damage Response ◽  
Dna Damage And Repair ◽  
Signaling Systems ◽  
Age Related ◽  
Complex Biological Process ◽  
Damage Response ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and physiological resilience. This is in part mediated by age-related aberrations in energy metabolism, mitochondrial function, protein folding and sorting, inflammatory activity and genomic stability. Indeed, an increased rate of unrepaired DNA damage is considered to be one of the ‘hallmarks’ of aging. Over the last two decades our appreciation of the complexity of GPCR signaling systems has expanded their functional signaling repertoire. One such example of this is the incipient role of GPCRs and GPCR-interacting proteins in DNA damage and repair mechanisms. Emerging data now suggest that GPCRs could function as stress sensors for intracellular damage, e.g., oxidative stress. Given this role of GPCRs in the DNA damage response process, coupled to the effective history of drug targeting of these receptors, this suggests that one important future activity of GPCR therapeutics is the rational control of DNA damage repair systems.

scholarly journals DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

2021 ◽  
Author(s):  
Jannigje Rachel Kok ◽  
Nelma M. Palminha ◽  
Cleide Dos Santos Souza ◽  
Sherif F. El-Khamisy ◽  
Laura Ferraiuolo
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Neuron Death ◽  
Damage Response ◽  
Motor Neuron Death ◽  
Sporadic Cases ◽  
Consistent Feature ◽  
Familial Als ◽  
Lateral Sclerosis

AbstractIncreasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.

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 DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

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