scholarly journals Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Swapnil Gupta ◽  
Panpan You ◽  
Tanima SenGupta ◽  
Hilde Nilsen ◽  
Kulbhushan Sharma
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
3D Models ◽  
Model Systems ◽  
Spinocerebellar Ataxias ◽  
C Elegans ◽  
Cellular Processes ◽  
Age Related ◽  
Damage Response ◽  
Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

scholarly journals C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1188 ◽  
Author(s):  
Carl Alexander Sandhof ◽  
Simon Oliver Hoppe ◽  
Jessica Tittelmeier ◽  
Carmen Nussbaum-Krammer
Keyword(s):  
Neurodegenerative Diseases ◽  
Model Organism ◽  
Model Systems ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Population Demographics ◽  
C Elegans ◽  
Age Related ◽  
Bona Fide ◽  
High Degree

A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.

scholarly journals Graptopetalum paraguayense Extract Ameliorates Proteotoxicity in Aging and Age-Related Diseases in Model Systems

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4317
Author(s):  
Yan-Xi Chen ◽  
Phuong Thu Nguyen Le ◽  
Tsai-Teng Tzeng ◽  
Thu-Ha Tran ◽  
Anh Thuc Nguyen ◽  
...  
Keyword(s):  
Model Systems ◽  
Wild Type ◽  
Nematode Caenorhabditis Elegans ◽  
Cancer Cell Growth ◽  
C Elegans ◽  
Age Related ◽  
Ampk Activity ◽  
Β Amyloid ◽  
Amp Activated Protein Kinase ◽  
U87 Cells

Declines in physiological functions are the predominant risk factors for age-related diseases, such as cancers and neurodegenerative diseases. Therefore, delaying the aging process is believed to be beneficial in preventing the onset of age-related diseases. Previous studies have demonstrated that Graptopetalum paraguayense (GP) extract inhibits liver cancer cell growth and reduces the pathological phenotypes of Alzheimer’s disease (AD) in patient IPS-derived neurons. Here, we show that GP extract suppresses β-amyloid pathology in SH-SYS5Y-APP695 cells and APP/PS1 mice. Moreover, AMP-activated protein kinase (AMPK) activity is enhanced by GP extract in U87 cells and APP/PS1 mice. Intriguingly, GP extract enhances autophagy in SH-SYS5Y-APP695 cells, U87 cells, and the nematode Caenorhabditis elegans, suggesting a conserved molecular mechanism by which GP extract might regulate autophagy. In agreement with its role as an autophagy activator, GP extract markedly diminishes mobility decline in polyglutamine Q35 mutants and aged wild-type N2 animals in C. elegans. Furthermore, GP extract significantly extends lifespan in C. elegans.

scholarly journals ESPO/ BIOLOGICAL SCIENCES SECTION SYMPOSIUM: EMERGING INSIGHTS IN INTERACTIONS AND NETWORKS IN THE BIOLOGY OF AGING DEVELOPING C. ELEGANS TO STUDY AGE-RELATED EXTRACELLULAR VESICLE SIGNALS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S424-S424
Author(s):  
Joshua Russell ◽  
Matt Kaeberlein
Keyword(s):  
Biological Sciences ◽  
Mammalian Cell Culture ◽  
Extracellular Vesicle ◽  
Model Systems ◽  
C Elegans ◽  
Physiological Processes ◽  
Age Related ◽  
Powerful Approach ◽  
Invertebrate Model ◽  
Biology Of Aging

Abstract All cells release vesicles into their extracellular environment. These extracellular vesicles (EVs) contain multiple classes of molecules, including nucleic acids, proteins, and lipids. EV-signaling has been shown to be impacted by many age-related physiological processes such as inflammation, mitochondrial stress, and autophagy as well as directly mediate critical functions in cellular senescence and aging. The isolation and analysis of EV cargos from mammalian cell culture and liquid biopsy samples has become a powerful approach for uncovering the messages that are packaged into these organelles. Caenorhabditis elegans is a premier model for dissecting the genetics of aging however, EV analysis has not been tenable in invertebrate model systems due to lack of methods for obtaining sufficient amounts of pure EVs. We developed a method for isolating pure EVs from C. elegans with yields sufficient for mass spectrometry and RNAseq. Here we present the analysis of the genetic and protein cargos of EVs collected from wild type and long-lived mutants collected at different time points across their lifespans. As the first investigation of age-related EV signals in an invertebrate model system we believe these results will provide insights into cell non-autonomous mechanisms of aging.

scholarly journals In vivo analysis of FANCD2 recruitment at meiotic DNA breaks in Caenorhabditis elegans

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Marcello Germoglio ◽  
Anna Valenti ◽  
Ines Gallo ◽  
Chiara Forenza ◽  
Pamela Santonicola ◽  
...  
Keyword(s):  
Dna Repair ◽  
Caenorhabditis Elegans ◽  
Genome Stability ◽  
Genetic Interaction ◽  
Model Systems ◽  
Dna Breaks ◽  
Strand Breaks ◽  
C Elegans ◽  
In Vivo Analysis

AbstractFanconi Anemia is a rare genetic disease associated with DNA repair defects, congenital abnormalities and infertility. Most of FA pathway is evolutionary conserved, allowing dissection and mechanistic studies in simpler model systems such as Caenorhabditis elegans. In the present study, we employed C. elegans to better understand the role of FA group D2 (FANCD2) protein in vivo, a key player in promoting genome stability. We report that localization of FCD-2/FANCD2 is dynamic during meiotic prophase I and requires its heterodimeric partner FNCI-1/FANCI. Strikingly, we found that FCD-2 recruitment depends on SPO-11-induced double-strand breaks (DSBs) but not RAD-51-mediated strand invasion. Furthermore, exposure to DNA damage-inducing agents boosts FCD-2 recruitment on the chromatin. Finally, analysis of genetic interaction between FCD-2 and BRC-1 (the C. elegans orthologue of mammalian BRCA1) supports a role for these proteins in different DSB repair pathways. Collectively, we showed a direct involvement of FCD-2 at DSBs and speculate on its function in driving meiotic DNA repair.

scholarly journals Endonuclease G promotes autophagy by suppressing mTOR signaling and activating the DNA damage response

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wenjun Wang ◽  
Jianshuang Li ◽  
Junyang Tan ◽  
Miaomiao Wang ◽  
Jing Yang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Glycogen Synthase ◽  
Endonuclease Activity ◽  
Phosphatidylinositol 3 Kinase ◽  
Endonuclease G ◽  
C Elegans ◽  
Cellular Processes ◽  
Damage Response ◽  
Type 3

AbstractEndonuclease G (ENDOG), a mitochondrial nuclease, is known to participate in many cellular processes, including apoptosis and paternal mitochondrial elimination, while its role in autophagy remains unclear. Here, we report that ENDOG released from mitochondria promotes autophagy during starvation, which we find to be evolutionally conserved across species by performing experiments in human cell lines, mice, Drosophila and C. elegans. Under starvation, Glycogen synthase kinase 3 beta-mediated phosphorylation of ENDOG at Thr-128 and Ser-288 enhances its interaction with 14-3-3γ, which leads to the release of Tuberin (TSC2) and Phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34) from 14-3-3γ, followed by mTOR pathway suppression and autophagy initiation. Alternatively, ENDOG activates DNA damage response and triggers autophagy through its endonuclease activity. Our results demonstrate that ENDOG is a crucial regulator of autophagy, manifested by phosphorylation-mediated interaction with 14-3-3γ, and its endonuclease activity-mediated DNA damage response.

scholarly journals Metabolism, Genomics, and DNA Repair in the Mouse Aging Liver

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Michel Lebel ◽  
Nadja C. de Souza-Pinto ◽  
Vilhelm A. Bohr
Keyword(s):  
Dna Repair ◽  
Point Mutations ◽  
Dna Lesions ◽  
Model Systems ◽  
Rodent Models ◽  
Waste Products ◽  
Related Disease ◽  
Age Related ◽  
Significant Impairment ◽  
And Function

The liver plays a pivotal role in the metabolism of nutrients, drugs, hormones, and metabolic waste products, thereby maintaining body homeostasis. The liver undergoes substantial changes in structure and function within old age. Such changes are associated with significant impairment of many hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. It has become clear, using rodent models as biological tools, that genetic instability in the form of gross DNA rearrangements or point mutations accumulate in the liver with age. DNA lesions, such as oxidized bases or persistent breaks, increase with age and correlate well with the presence of senescent hepatocytes. The level of DNA damage and/or mutation can be affected by changes in carcinogen activation, decreased ability to repair DNA, or a combination of these factors. This paper covers some of the DNA repair pathways affecting liver homeostasis with age using rodents as model systems.

scholarly journals A cell-based platform for oxidative stress monitoring in motor neurons using genetically encoded biosensors of H2O2

2021 ◽  
Author(s):  
Elizaveta I. Ustyantseva ◽  
Suren M. Zakian ◽  
Sergey P. Medvedev
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Motor Neurons ◽  
Model Systems ◽  
Patient Specific ◽  
Ipsc Line ◽  
Stress Monitoring ◽  
A Cell ◽  
Lateral Sclerosis

ABSTRACTBackgroundOxidative stress plays an important role in the development of neurodegenerative diseases: it either can be the initiator or part of a pathological cascade leading to the neuron’s death. Although a lot of methods are known for oxidative stress study, most of them operate on non-native cellular substrates or interfere with the cell functioning. Genetically encoded (GE) biosensors of oxidative stress demonstrated their general functionality and overall safety in various live systems. However, there is still insufficient data regarding their use for research of disease-related phenotypes in relevant model systems, such as human cells.MethodsWe applied CRISPR/Cas9 genome editing to introduce mutations (c.272A>C and c.382G>C) in the associated with amyotrophic lateral sclerosis SOD1 gene of induced pluripotent stem cells (iPSC) obtained from a healthy individual. Using CRISPR/Cas9, we modified these mutant iPSC lines, as well as the parental iPSC line, and a patient-specific SOD1D91A/D91A iPSC line with ratiometric GE biosensors of cytoplasmic (Cyto-roGFP2-Orp1) and mitochondrial (Mito-roGFP2-Orp1) H2O2. The biosensors sequences along with a specific transactivator for doxycycline-controllable expression were inserted in the “safe harbor” AAVS1 (adeno-associated virus site 1) locus. We differentiated these transgenic iPSCs into motor neurons and investigated the functionality of the biosensors in such a system. We measured relative oxidation in the cultured motor neurons and its dependence on culture conditions, age, and genotype, as well as kinetics of H2O2 elimination in real-time.ResultsWe developed a cell-based platform consisting of isogenic iPSC lines with different genotypes associated with amyotrophic lateral sclerosis. The iPSC lines were modified with GE biosensors of cytoplasmic and mitochondrial H2O2. We provide proof-of-principle data showing that this approach may be suitable for monitoring oxidative stress in cell models of various neurodegenerative diseases as the biosensors reflect the redox state of neurons.ConclusionWe found that the GE biosensors inserted in the AAVS1 locus remain functional in motor neurons and reflect pathological features of mutant motor neurons, although the readout largely depends on the severity of the mutation.

scholarly journals Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

Open Biology ◽  
2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Anna Ainslie ◽  
Wouter Huiting ◽  
Lara Barazzuol ◽  
Steven Bergink
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
Genome Stability ◽  
Genome Instability ◽  
Copy Number Variations ◽  
Therapeutic Interventions ◽  
Gene Copy ◽  
Protein Homeostasis ◽  
Age Related

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

Sleep disorders in neurodegenerative diseases other than Parkinson disease and multiple system atrophy

2017 ◽  
Author(s):  
Raffaele Manni ◽  
Michele Terzaghi
Keyword(s):  
Neurodegenerative Diseases ◽  
Sleep Disorders ◽  
Neurodegenerative Disorders ◽  
Sleep Problems ◽  
Lewy Bodies ◽  
Corticobasal Degeneration ◽  
Spinocerebellar Ataxias ◽  
Age Related ◽  
Key Points ◽  
Sleep Alterations

This chapter examines sleep–wake disturbances occurring in the most common neurodegenerative disorders. It reviews sleep alterations in Alzheimer disease and dementia with Lewy bodies. It also discusses sleep problems in progressive supranuclear palsy, corticobasal degeneration, Huntington disease, and spinocerebellar ataxias. Status dissociatus as an extreme form of sleep alteration in advanced neurodegenerative diseases is also considered. The chapter reviews the key points for the treatment of disrupted sleep in neurodegenerative disorders, with a focus on pharmacological and nonpharmacological interventions to improve sleep continuity. It also summarizes paraphysiological age-related changes in sleep patterns and discusses indications and procedures for clinical and instrumental assessment of sleep disorders in neurodegenerative disorders.

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.

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