Semaglutide and the pathogenesis of progressive neurodegenerative disease: the central role of mitochondria.

Mitochondria: The Next (Neurode)Generation

Activation of Nrf2 signaling as a common treatment of neurodegenerative diseases.

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges.

This Special Issue comprises nine reviews offering perspectives from the development of neurodegeneration in different pathologies to neuronal protection, providing new views on the mechanism of neurodegeneration and associated processes and a summary of the progress in neuroscience. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions to The FEBS Journal.

Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases

Therapeutic Translation of iPSCs for Treating Neurological Disease

Organelle transport in neuronal processes is central to the organization, developmental fate, and functions of neurons. Organelles must be transported through the slender, highly branched neuronal processes, making the axonal transport vulnerable to any perturbation. However, some intracellular structures like mitochondria are able to considerably modify their volume. We therefore hypothesized that swollen mitochondria could impair the traffic of other organelles in neurite shafts. To test this hypothesis, we have investigated the effects of mitochondrial swellers on the organelle traffic. Our data demonstrate that treatment of neurons with potassium ionophore valinomycin led to the fast time-dependent inhibition of organelle movement in cerebellar granule neurons. Similar inhibition was observed in neurons treated with the inhibitors of the mitochondrial respiratory chain, sodium azide and antimycin, which also induced swelling. No decrease in the motility of organelles was observed in cultures treated with inhibitors of ATP production or transport, oligomycin or bongkrekic acid, suggesting that inhibition of the ATP-generating activity itself without swelling does not affect the motility of organelles. The effect of swellers on the traffic was more important in thin processes, thus indicating the role of steric hindrance of swollen mitochondria. We propose that the size and morphology of the transported cargo is also relevant for seamless axonal transport and speculate that mitochondrial swelling could be one of the reasons for impaired organelle transport in neuronal processes.

Aging is the strongest risk factor for most neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. As the aging population is increasing, these neurodegenerative disorders are becoming major social issues in many countries. Interestingly, these diseases share a common pathological phenotype; the accumulation of misfolded and aggregated proteins in the brain. Mounting evidence suggests that there are mechanistic links between toxic protein aggregation and neurodegenerative diseases. With a better understanding of the pathogenesis of these disorders, discovery efforts for disease-modifying therapeutics have markedly increased in recent years. This special issue, titled ‘Neurodegenerative diseases and their therapeutic approaches', discusses the underlying pathogenic mechanisms and therapeutic implications for AD and other age-associated neurodegenerative disorders. Aaron Ciechanover and Yong Tae Kwon provide a comprehensive overview of the proteolytic pathways in neurons, with a special emphasis on the ubiquitin–proteasome system (UPS), chaperone-mediated autophagy and macroautophagy. They also discuss the role of protein quality control in the degradation of pathogenic proteins involved in several neurodegenerative diseases. The initial discovery of the UPS was published by Dr Aaron Ciechanover, who won a Nobel Prize in 20041 (http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2004/ciechanover-lecture.pdf). Among the age-associated neurodegenerative diseases, AD is the most common neurodegenerative disease. Its symptoms include cognitive impairment, disturbance of the sleep–wake cycle and circadian rhythms, and dysfunctions of metabolism, such as insulin-resistance and mitochondrial dysfunction. The pathological hallmarks of AD are intracellular neurofibrillary tangles, extracellular senile plaques and neuronal cell loss. Neurofibrillary tangles are mainly composed of hyperphosphorylated tau, and the major component of senile plaques is amyloid-β (Aβ) peptides. Many lines of evidence have shown the strong association between the two aggregated molecules, Aβ and tau, and AD pathogenesis. Holtzman's group reviews multiple molecular mechanisms by which sleep disturbance and disruption of circadian rhythms may affect AD pathogenesis. In addition, they discuss potential therapeutic strategies for AD by targeting the circadian clock and sleep–wake system. Bhumsoo Kim and Eva L Feldman focus on the dysfunction of insulin signaling in AD pathogenesis. Insulin signaling has diverse roles in the brain, such as cognition, memory, synaptic plasticity and neurogenesis. As AD patients show the disrupted glucose metabolism in the brain, it is reasonable to link insulin resistance and AD pathogenesis. The authors also suggest that several diabetes therapies targeting insulin signaling may have potential therapeutic benefits in AD patients. Mook-Jung's gourp review the mitochondrial dysfunction in several neurodegenerative diseases, including AD. Reactive oxygen species (ROS) is a well-known stress factor for the central nervous system. ROS induces mutations in mitochondrial genes, leading to more ROS generation by exacerbating mitochondrial dysfunction. This vicious cycle between ROS and mitochondrial dysfunction further stresses neurons, eventually leading to cell death. Antioxidant therapy restoring mitochondrial function might be one of potential therapeutic strategies to treat AD and other neurodegenerative disorders. Proper maintenance of neuronal circuits is critical for learning and memory. The loss of neurons and neuronal processes directly contributes to cognitive declines in AD. Because many clinical trials with small molecule approaches, as well as anti-Aβ immunotherapy has failed, cell replacement therapy using human embryonic stem cell- or induced pluripotent stem cell -derived neural cells is gaining attention as a potential treatment for AD. Huang's group reviews the current status and future prospects of stem cell therapy for AD and other related disorders. Because AD and other age-associated neurodegenerative disorders are chronic diseases, many factors might be involved in the onset and progression of these diseases. The five articles in this special issue provide comprehensive reviews of the multiple pathogenic mechanisms underlying AD and related neurodegenerative disorders. In addition, each review suggests potential therapeutic targets for the treatment of AD. Taken together, this special issue, titled ‘Neurodegenerative diseases and their therapeutic approaches', in EMM is an invaluable resource for understanding the current status and future perspectives of AD and related neurodegenerative disorders.

Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds

Introduction During the past few years there have been notable advances towards understanding the molecular defects underlying the pathogenesis of chronic neurodegenerative disorders such as Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (AM). For example, in 1993, the discovery of the genetic abnormality in HD was reported (an increase in CAC repeats in a gene encoding an unknown protein) [l], while in the same year researchers demonstrated the existence of point mutations in the gene encoding the enzyme Cu/Zn superoxide dismutase (SOD-1) in some familial AI,S patients 121. Rut despite these findings, the biochemical mechanisms whereby molecular defects can lead to the slowly progressive neuronal degeneration with age-dependent onset, characteristic of these neurodegenerative disorders, still remain an enigma. However, evidence has been mounting in support of the proposition that defects in mitochondrial energy metabolism play an intrinsic role. Further, strong evidence is emerging indicating that this mitochondrial energy dysfunction may result from oxidative damage to mitochondrial DNA and other neuronal macromolecules, and excitotoxic mechanisms have also been linked with mitochondrial dysfunction. Consequently, it has been proposed that a progressive impairment of mitochondrial oxidative phosphorylation may secondarily result in slow excitotoxic neuronal death, by making neurons more vulnerable to endogenous levels of glutamate [3,4]. In this paper, we will review evidence supporting roles for oxidative damage and mitochondrial energy dysfunction in the pathogenesis of neurodegenerative diseases, as

Editorial: A Trends guide to Neurodegenerative Disease and Repair

Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: Etiologies and therapeutic strategies

The abnormal of mitochondrial morphology and function discover in many neurodegenerative disorders,including Parkinson's disease (PD) and Alzheimer's disease (AD) which are extremely common diseases,also including rare types of neurodegenerative diseases,such as Huntington s disease (HD),amyotrophic lateral sclerosis (ALS),spinocerebellar ataxia (SCA) and so on.The specific changes of mitochondrial morphology and function or mitochondrial defects in some diseases have been demonstrated in vivo and vitro experiments.Mitochondrial defects that lead to the damage of normal neurons and the dysfunction of nervous system,eventually result in the neurodegenerative disorders.Here is to make a review of abnormalities of mitochondrial function and morphology and relationships between with the degenerative diseases. Key words: Mitochondria ; Neurodegenerative diseases

Background:Adult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited.Objective:We examined the potential association between long-term exposure to particulate matter in aerodynamic diameter [fine particulate matter ()] and disease aggravation in Alzheimer’s (AD) and Parkinson’s (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation.Methods:We used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000–2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual concentrations estimated by a prediction model at a resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y exposure. We allowed for nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders.Results:We found a positive nonlinear association that plateaued above (, 95% CI: 1.04, 1.14 for a increase from 8.1 to ). We also found a linear positive association (, 95% CI: 1.01, 1.09 per increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes.Conclusion:Our findings suggest that annual increase in county-level concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual concentration in our study was , below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425