Crosstalk between the DNA damage response and cellular senescence drives aging and age-related diseases.

Cellular senescence is a crucial process of irreversible cell-cycle arrest, in which cells remain alive, but permanently unable to proliferate in response to distinct types of stressors. Accumulating evidence suggests that DNA damage builds over time and triggers DNA damage response signaling, leading to cellular senescence. Cellular senescence serves as a platform for the perpetuation of inflammatory responses and is central to numerous age-related diseases. Defects in DNA repair genes or senescence can cause premature aging disease. Therapeutic approaches limiting DNA damage or senescence contribute to a rescued phenotype of longevity and neuroprotection, thus suggesting a mechanistic interaction between DNA damage and senescence. Here, we offer a unique perspective on the crosstalk between the DNA damage response pathway and senescence as well as their contribution to age-related diseases. We further summarize recent progress on the mechanisms and therapeutics of senescence, address existing challenges, and offering new insights and future directions in the senescence field.

The Association between Long Non-Coding RNAs and Alzheimer's Disease.

Neurodegeneration occurs naturally as humans age, but the presence of additional pathogenic mechanisms yields harmful and consequential effects on the brain. Alzheimer's disease (AD), the most common form of dementia, is a composite of such factors. Despite extensive research to identify the exact causes of AD, therapeutic approaches for treating the disease continue to be ineffective, indicating important gaps in our understanding of disease mechanisms. Long non-coding RNAs (lncRNAs) are an endogenous class of regulatory RNA transcripts longer than 200 nucleotides, involved in various regulatory networks, whose dysregulation is evident in several neural and extraneural diseases. LncRNAs are ubiquitously expressed across all tissues with a wide range of functions, including controlling cell differentiation and development, responding to environmental stimuli, and other physiological processes. Several lncRNAs have been identified as potential contributors in worsening neurodegeneration due to altered regulation during abnormal pathological conditions. Within neurological disease, lncRNAs are prime candidates for use as biomarkers and pharmacological targets. Gender-associated lncRNA expression is altered in a gender-dependent manner for AD, suggesting more research needs to be focused on this relationship. Overall, research on lncRNAs and their connection to neurodegenerative disease is growing exponentially, as commercial enterprises are already designing and employing RNA therapeutics. In this review we offer a comprehensive overview of the current state of knowledge on the role of lncRNAs in AD and discuss the potential implications of lncRNA as potential therapeutic targets and diagnostic biomarkers in patients with Alzheimer's disease.

An Overview of UBTF Neuroregression Syndrome.

Recently, a recurrent de novo dominant mutation in UBTF (c.628G>A, p.Glu210Lys; UBTF E210K) was identified as the cause of a neurological disorder which has been named UBTF Neuroregression Syndrome (UNS), or Childhood-Onset Neurodegeneration with Brain Atrophy (CONDBA). To date, only 17 cases have been reported worldwide. The molecular etiology is a pathogenic variant, E210K, within the HMG-box 2 of Upstream Binding Transcription Factor (UBTF). UBTF, a nucleolar protein, plays an important role in ribosomal RNA (rRNA) synthesis, nucleolar integrity, and cell survival. This variant causes unstable preinitiation complexes to form, resulting in altered rDNA chromatin structures, rRNA dysregulation, DNA damage, and ultimately, neurodegeneration. Defining clinical characteristics of the disorder include but are not limited to developmental regression beginning at approximately three years of age, progressive motor dysfunction, declining cognition, ambulatory loss, and behavioral problems. Histological and neuroimaging abnormalities include cortical atrophy, white matter deficits, and enlarged ventricles. Herein, we present a detailed overview of all published cases as well as the functional roles of UBTF to better understand the pathophysiology. Bringing undiagnosed cases to the attention of clinicians and researchers by making them aware of the clinical features will improve research and support the development of therapeutic interventions.

Coherent ultrafast photoemission from a single quantized state of a one-dimensional emitter.

Femtosecond laser-driven photoemission source provides an unprecedented femtosecond-resolved electron probe not only for atomic-scale ultrafast characterization but also for free-electron radiation sources. However, for conventional metallic electron source, intense lasers may induce a considerable broadening of emitting energy level, which results in large energy spread (>600 milli-electron volts) and thus limits the spatiotemporal resolution of electron probe. Here, we demonstrate the coherent ultrafast photoemission from a single quantized energy level of a carbon nanotube. Its one-dimensional body can provide a sharp quantized electronic excited state, while its zero-dimensional tip can provide a quantized energy level act as a narrow photoemission channel. Coherent resonant tunneling electron emission is evidenced by a negative differential resistance effect and a field-driven Stark splitting effect. The estimated energy spread is ~57 milli-electron volts, which suggests that the proposed carbon nanotube electron source may promote electron probe simultaneously with subangstrom spatial resolution and femtosecond temporal resolution.

Behavioral and molecular effects of Ubtf knockout and knockdown in mice.

The UBTF E210K neuroregression syndrome is caused by de novo dominant mutations in UBTF (NM_014233.3:c.628G > A, p.Glu210Lys). In humans, onset is typically at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Other potentially pathogenic UBTF variants have been reported in humans with severe neurological disease and it remains undetermined if the UBTF E210K mutation operates via gain- and/or loss-of-function. Here we examine the behavioral, cognitive, motor, and molecular effects of Ubtf knockout and knockdown in mice as a means of gauging the role of loss-of-function in humans. Ubtf+/- mice show progression of behavioral (dominance tube), cognitive (cross maze), and mild motor abnormalities from 3 to 18 months. At 18 months, Ubtf+/- mice had more slips on a raised 9-mm round beam task, shorter latencies to fall on the accelerated rotarod, reduced open field vertical and jump counts, and significant deficits in spatial learning and memory. Via crosses to Nestin-Cre (NesCre) mice we found that homozygous Ubtf deletion limited to the central nervous system was embryonic lethal. Tamoxifen-induced homozygous knockdown of Ubtf in adult mice with the Cre-ERT2 system was associated with precipitous deterioration in neurological functioning. At the molecular level, 18-month-old Ubtf+/- mice showed mild increases in cerebellar 53BP1 immunoreactivity. These findings show that UBTF is essential for embryogenesis and survival in adults, and the deleterious effects of UBTF haploinsufficiency progress with age. Loss-of-function mechanisms may contribute, in part, to the human UBTF E210K neuroregression syndrome.

The Expression of Pyroptosis-Related Gene May Influence the Occurrence, Development, and Prognosis of Uterine Corpus Endometrial Carcinoma.

Background: Increasing evidence has demonstrated that pyroptosis exerts key roles in the occurrence, development, and prognosis of uterine corpus endometrial carcinoma (UCEC). However, the mechanism of pyroptosis and its predictive value for prognosis remain largely unknown. Methods: UCEC data were acquired from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes in UCEC vs. normal cases were selected to perform a weighted correlation network analysis (WGCNA). Forty-two UCEC-associated pyroptosis-related genes were identified via applying differential expression analysis. Protein-protein interaction (PPI) and gene correlation analyses were applied to explore the relationship between 21 UCEC key genes and 42 UCEC-associated pyroptosis-related genes. The expression of 42 UCEC-associated pyroptosis-related genes of different grades was also calculated. The immune environment of UCEC was evaluated. Furthermore, pyroptosis-related genes were filtered out by the co-expression. Univariate and a least absolute shrinkage and selection operator (LASSO) Cox analyses were implemented to yield a pyroptosis-related gene model. We also performed consensus classification to regroup UCEC samples into two clusters. A clinically relevant heatmap and survival analysis curve were implemented to explore the clinicopathological features and relationship between two clusters. Furthermore, a Kaplan-Meier survival analysis was implemented to analyze the risk model. Results: Twenty-one UCEC key genes and 42 UCEC-associated pyroptosis-related genes were identified. The PPI and gene correlation analysis showed a clear relationship. The expression of 42 UCEC-associated pyroptosis-related genes of different grades was also depicted. A risk model based on pyroptosis-related genes was then developed to forecast overall survival among UCEC patients. Finally, Cox regression analysis verified this model as an independent risk factor for UCEC patients. Conclusions: The expression of pyroptosis-related gene may influence UCEC occurrence, development, and prognosis.

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.

BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31. OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

Blue, green, and grey water footprints assessment for paddy irrigation-drainage system.

Water footprint (WF) quantifies the impact of paddy field evapotranspiration (ET) and non-point source pollution on water resources and is an evaluation index for water sustainability. However, it is difficult to measure accurately using the existing method, which is based on parameter assumption without considering the field water conditions. In this study, a generic and physically based method for blue, green, and grey water accounting in paddy rice cultivation is introduced. We conducted field experiments using the common flood irrigation (CFI) and water-saving irrigation (SWI) modes in Nanjing, East China. By tracing the sources of ET and the migration process of multiple pollutants (TN, TP, NH4+-N, and NO3--N), the characteristics of blue-green water consumption and the actual amount of water required to dilute pollutants at different growth stages of rice under CFI and SWI were analyzed. The WF of paddy rice was 1000 m3/t (49% WFgreen, 17% WFblue, 34% WFgrey) and 910 m3/t (50% WFgreen, 10% WFblue, 40% WFgrey) for CFI and SWI, respectively. The WF for paddy rice production was reduced by approximately 9% under SWI compared to CFI, with declines of 47% for WFblue and 8% for WFgreen. The SWI mode changed the ratio of blue to green water fluxes in field water by reducing irrigation during non-critical periods, and green water was used preferentially to enhance its utility. This conceptual method is the first to describe the formation mechanism of blue, green, and grey WFs in paddy systems. It can be extended to different scales and agro-ecosystems that show the influence of crop cultivation on water resources.

Nanocone-Shaped Carbon Nanotubes Field-Emitter Array Fabricated by Laser Ablation.

The nanocone-shaped carbon nanotubes field-emitter array (NCNA) is a near-ideal field-emitter array that combines the advantages of geometry and material. In contrast to previous methods of field-emitter array, laser ablation is a low-cost and clean method that does not require any photolithography or wet chemistry. However, nanocone shapes are hard to achieve through laser ablation due to the micrometer-scale focusing spot. Here, we develop an ultraviolet (UV) laser beam patterning technique that is capable of reliably realizing NCNA with a cone-tip radius of ≈300 nm, utilizing optimized beam focusing and unique carbon nanotube-light interaction properties. The patterned array provided smaller turn-on fields (reduced from 2.6 to 1.6 V/µm) in emitters and supported a higher (increased from 10 to 140 mA/cm2) and more stable emission than their unpatterned counterparts. The present technique may be widely applied in the fabrication of high-performance CNTs field-emitter arrays.

Palmaris Brevis Syndrome: A Treatable Pseudodystonia.

Background: Palmaris brevis syndrome, a pseudodystonia characterized by abnormal involuntary contractions of the palmaris brevis muscle which resides in the hypothenar eminence, is believed to be due to compressive irritation of motor fibers which arise from the superficial branch of the ulnar nerve. Case report: Herein, we review the origins, differential diagnosis and pathophysiology of the palmaris brevis syndrome, and effective treatment of a patient with workplace modifications and injections of botulinum toxin type A. Discussion: Prompt diagnosis of the palmaris brevis syndrome facilitates effective treatment and resolution. Highlights: Like the task-specific hand dystonias seen in writers and musicians, palmaris brevis syndrome, a pseudodystonia, may be caused and aggravated by extreme repetitive use. Here, we report a case of palmaris brevis syndrome apparently triggered by high-volume use of a pipette and computer mouse and review relevant clinical facets from previously published cases. Treatment must include workplace modifications and may include injections of botulinum toxin.

Stable Field Emission from Vertically Oriented SiC Nanoarrays.

Silicon carbide (SiC) nanostructure is a type of promising field emitter due to high breakdown field strength, high thermal conductivity, low electron affinity, and high electron mobility. However, the fabrication of the SiC nanotips array is difficult due to its chemical inertness. Here we report a simple, industry-familiar reactive ion etching to fabricate well-aligned, vertically orientated SiC nanoarrays on 4H-SiC wafers. The as-synthesized nanoarrays had tapered base angles >60°, and were vertically oriented with a high packing density >107 mm-2 and high-aspect ratios of approximately 35. As a result of its high geometry uniformity-5% length variation and 10% diameter variation, the field emitter array showed typical turn-on fields of 4.3 V µm-1 and a high field-enhancement factor of ~1260. The 8 h current emission stability displayed a mean current fluctuation of 1.9 ± 1%, revealing excellent current emission stability. The as-synthesized emitters demonstrate competitive emission performance that highlights their potential in a variety of vacuum electronics applications. This study provides a new route to realizing scalable field electron emitter production.

Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1ß production in the 5xFAD gut. Consistent with our hypothesis, increased gut-microbial-inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1ß production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut-microbial-inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

Maternal fever during preconception and conception is associated with congenital heart diseases in offspring: An updated meta-analysis of observational studies.

BACKGROUNDS: Many studies have evaluated the effect of maternal fever on the development risk of congenital heart diseases (CHDs) in offspring, but the findings were inconsistent. Furthermore, a complete overview of the existing data was also missing. Therefore, we intend to provide updated epidemiologic evidence to estimate the association between maternal fever and the risk of overall CHDs and specific CHD phenotypes in offspring. METHODS: Pubmed, Embase, and Web of Science were searched through March 2020 to identify eligible studies that assessed the association between maternal fever and CHDs risk in offspring. The summary risk estimates were calculated using random-effects models. Potential heterogeneity source was explored by subgroup analyses and potential publication bias was assessed by Begg funnel plots and Begg rank correlation test. RESULTS: Sixteen studies involving 31,922 CHDs cases among 183,563 participants were included in this meta-analysis. Overall, mothers who had a fever experience during preconception and conception periods had a significantly higher risk of overall CHDs in offspring (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.21-1.73) when compared with those who did not have a fever experience. For specific CHD phenotypes in offspring, a statistically significant association was found between maternal fever and risk of conotruncal defects (CTD) (OR = 1.38, 95%CI: 1.01-1.89), atrial septal defects (ASD) (OR = 1.48, 95% CI: 1.01-2.17), transposition of the great vessels (TGA) (OR = 1.81, 95% CI: 1.14-2.88), and right ventricular outflow tract obstruction (RVOTO) (OR = 1.66, 95% CI: 1.04-2.65). Relevant heterogeneity moderators have been identified by subgroup analyses, and sensitivity analyses yielded consistent results. CONCLUSIONS: Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, our review indicates that maternal fever is significantly associated with the risk of CHDs in offspring, which highlights that preventing maternal fever during the preconception and conception periods play an important role in decreasing the risk of CHDs in offspring. However, given the limited number of current case-control studies, larger-sample prospective studies are required to further confirm our results. Besides, due to the underlying mechanisms between maternal fever and the risk of specific CHD phenotypes in offspring are still unreported, more research is needed to explore the possible mechanisms.

DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for a majority of dementia cases. AD is characterized by progressive neuronal death associated with neuropathological lesions consisting of neurofibrillary tangles and senile plaques. While the pathogenesis of AD has been widely investigated, significant gaps in our knowledge remain about the cellular and molecular mechanisms promoting AD. Recent studies have highlighted the role of DNA damage, particularly DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of neurodegenerative diseases. In the present study, we tested the hypothesis that accumulation of DNA DSB plays an important role in AD pathogenesis. To test our hypothesis, we examined DNA DSB expression and DNA repair function in the hippocampus of human AD and non-AD brains by immunohistochemistry, ELISA, and RT-qPCR. We observed increased DNA DSB accumulation and reduced DNA repair function in the hippocampus of AD brains compared to the non-AD control brains. Next, we found significantly increased levels of DNA DSB and altered levels of DNA repair proteins in the hippocampus of 5xFAD mice compared to non-transgenic mice. Interestingly, increased accumulation of DNA DSBs and altered DNA repair proteins were also observed in cellular models of AD. These findings provided compelling evidence that AD is associated with accumulation of DNA DSB and/or alteration in DSB repair proteins which may influence an important early part of the pathway toward neural damage and memory loss in AD.

Brain Selective Estrogen Treatment Protects Dopaminergic Neurons and Preserves Behavioral Function in MPTP-induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and loss of both motor and non-motor features. Several clinical and preclinical studies have provided evidence that estrogen therapy reduces the risk of PD but have limitations in terms of adverse peripheral effects. Therefore, we examined the potential beneficial effects of the brain-selective estrogen prodrug, 10ß, 17ß-dihydroxyestra-1,4-dien-3-one (DHED) on nigrostriatal dopaminergic neurodegeneration and behavioral abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wild-type mice were treated with daily subcutaneous injections of DHED (50 and 100 µg/kg) or vehicle for four weeks. To produce PD-like symptoms, mice were injected with MPTP (18 mg/kg in saline; intraperitoneally) four times at 2-hr intervals for one day. After behavioral examination, mice were sacrificed, and the brains were isolated for neurochemical and morphological examinations. MPTP injected mice exhibited loss of dopaminergic neurons and fibers in substantia nigra and striatum respectively, along with impaired motor function at day 7 post MPTP injection. These phenotypes were associated with significantly increased oxidative stress and inflammatory responses in the striatum regions. DHED treatments significantly mitigated behavioral impairments and dopaminergic neurodegeneration induced by MPTP. We further observed that DHED treatment suppressed oxidative stress and inflammation in the striatum of MPTP treated mice when compared to vehicle treated mice. In conclusions, our findings suggest that DHED protects dopaminergic neurons from MPTP toxicity in mouse model of PD and support a beneficial effect of brain-selective estrogen in attenuating neurodegeneration and motor symptoms in PD-related neurological disorders. Graphical Abstract.

Corrigendum to "N-Acetyl Cysteine as a Novel Polymethyl Methacrylate Resin Component: Protection against Cell Apoptosis and Genotoxicity".

[This corrects the article DOI: 10.1155/2019/1301736.].

Presynaptic PRRT2 Deficiency Causes Cerebellar Dysfunction and Paroxysmal Kinesigenic Dyskinesia.

PRRT2 loss-of-function mutations have been associated with familial paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis, and benign familial infantile seizures. Dystonia is the foremost involuntary movement disorder manifest by patients with PKD. Using a lacZ reporter and quantitative reverse-transcriptase PCR, we mapped the temporal and spatial distribution of Prrt2 in mouse brain and showed the highest levels of expression in cerebellar cortex. Further investigation into PRRT2 localization within the cerebellar cortex revealed that Prrt2 transcripts reside in granule cells but not Purkinje cells or interneurons within cerebellar cortex, and PRRT2 is presynaptically localized in the molecular layer. Analysis of synapses in the cerebellar molecular layer via electron microscopy showed that Prrt2-/- mice have increased numbers of docked vesicles but decreased vesicle numbers overall. In addition to impaired performance on several motor tasks, approximately 5% of Prrt2-/- mice exhibited overt PKD with clear face validity manifest as dystonia. In Prrt2 mutants, we found reduced parallel fiber facilitation at parallel fiber-Purkinje cell synapses, reduced Purkinje cell excitability, and normal cerebellar nuclear excitability, establishing a potential mechanism by which altered cerebellar activity promotes disinhibition of the cerebellar nuclei, driving motor abnormalities in PKD. Overall, our findings replicate, refine, and expand upon previous work with PRRT2 mouse models, contribute to understanding of paroxysmal disorders of the nervous system, and provide mechanistic insight into the role of cerebellar cortical dysfunction in dystonia.

The Role of Neurovascular System in Neurodegenerative Diseases.

The neurovascular system (NVS), which consisted of neurons, glia, and vascular cells, is a functional and structural unit of the brain. The NVS regulates blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), thereby maintaining the brain's microenvironment for normal functioning, neuronal survival, and information processing. Recent studies have highlighted the role of vascular dysfunction in several neurodegenerative diseases. This is not unexpected since both nervous and vascular systems are functionally interdependent and show close anatomical apposition, as well as similar molecular pathways. However, despite extensive research, the precise mechanism by which neurovascular dysfunction contributes to neurodegeneration remains incomplete. Therefore, understanding the mechanisms of neurovascular dysfunction in disease conditions may allow us to develop potent and effective therapies for prevention and treatment of neurodegenerative diseases. This review article summarizes the current research in the context of neurovascular signaling associated with neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss the potential implication of neurovascular factor as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions. Graphical Abstract.

DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases.

The complexity of neurodegeneration restricts the ability to understand and treat the neurological disorders affecting millions of people worldwide. Therefore, there is an unmet need to develop new and more effective therapeutic strategies to combat these devastating conditions and that will only be achieved with a better understanding of the biological mechanism associated with disease conditions. Recent studies highlight the role of DNA damage, particularly, DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases. This is not unexpected because neurons are prone to DNA damage due to their non-proliferative nature and high metabolic activity. However, it is not clear if DSBs is a primary driver of neuronal loss in disease conditions or simply occurs concomitant with disease progression. Here, we provide evidence that supports a critical role of DSBs in the pathogenesis of the neurodegenerative diseases. Among different kinds of DNA damages, DSBs are the most harmful and perilous type of DNA damage and can lead to cell death if left unrepaired or repaired with error. In this review, we explore the current state of knowledge regarding the role of DSBs repair mechanisms in preserving neuronal function and survival and describe how DSBs could drive the molecular mechanisms resulting in neuronal death in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also discuss the potential implications of DSBs as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions.