Parkinsons disease(PD)is a chronic,progressive neurodegenerative disorder characterized by both motor and non-motor symptoms.Pain,a key component of PDs non-motor symptoms,was first documented by Charcot in 1872 as a ...Parkinsons disease(PD)is a chronic,progressive neurodegenerative disorder characterized by both motor and non-motor symptoms.Pain,a key component of PDs non-motor symptoms,was first documented by Charcot in 1872 as a potential correlate of the disease.While pharmacological and surgical interventions have gained traction in managing PD-related pain,the therapeutic framework remains inconsistent.Understanding the pathogenesis and contributing factors of PD pain is crucial for developing novel therapies and refining disease identification and treatment protocols.This review examines the potential mechanisms and influencing factors of PD-associated pain,with the aim of identifying new therapeutic targets for PD pain.展开更多
Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson...Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.展开更多
Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include...Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include disturbances in sleep,gastrointestinal function,and olfaction.PD misdiagnosis rates have been reported to reach approximately 30%,partly owing to the heterogeneity of parkinsonism with non-PD pathologies,and the differential diagnosis of PD from neurodegenerative diseases such as multiple systemic atrophy(MSA)and progressive supranuclear palsy poses another unmet need.展开更多
Neurodegenerative diseases are a growing burden on healthcare systems.Patients with Alzheimer’s or Parkinson’s diseases(AD or PD)are desperately waiting for innovative solutions that are slow to come,despite several...Neurodegenerative diseases are a growing burden on healthcare systems.Patients with Alzheimer’s or Parkinson’s diseases(AD or PD)are desperately waiting for innovative solutions that are slow to come,despite several decades of research worldwide.In 2021 and again in 2023,two monoclonal antibodies,aducanumab and lecanemab,have been approved by the U.S.Food and Drug Administration,and a third,donanemab,is currently under review.However,these treatments have very limited efficacy on cognitive functions and are accompanied by major side effects:amyloid-related imaging abnormalities,microhemorrhages,and accelerated brain volume loss(Høilund-Carlsen et al.,2024).展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor...Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).展开更多
Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis...Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.展开更多
In recent years,rising life expectancy has led to a significant increase in the prevalence of neurodegenerative disorders,including Alzheimer’s disease(AD),Parkinson’s disease,and age-related cognitive decline.Addit...In recent years,rising life expectancy has led to a significant increase in the prevalence of neurodegenerative disorders,including Alzheimer’s disease(AD),Parkinson’s disease,and age-related cognitive decline.Additionally,other neurological conditions such as glioblastoma,the most common and aggressive brain tumor in adults have been more frequently reported in aging populations.The brain itself is highly vulnerable to age-related changes,particularly disruptions in homeostatic regulation,which further contribute to its functional decline and heightened susceptibility to disease.This has led to a surge of interest in understanding the cellular and molecular mechanisms driving these changes.展开更多
A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative...A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.展开更多
Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson'...Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).展开更多
Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticula...Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).展开更多
The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzh...The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.展开更多
N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory lo...N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.展开更多
Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’...Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.展开更多
BACKGROUND Parkinson’s disease(PD)is a common neurodegenerative disorder in the elderly population.Non-motor symptoms such as anxiety and depression are often subtle,hindering early detection and intervention,yet the...BACKGROUND Parkinson’s disease(PD)is a common neurodegenerative disorder in the elderly population.Non-motor symptoms such as anxiety and depression are often subtle,hindering early detection and intervention,yet they markedly affect quality of life and clinical outcomes.AIM To investigate the prevalence of anxiety and depression in elderly PD patients,identify associated risk factors,and assess their relationship with fatigue severity.METHODS A cross-sectional analysis was conducted in 123 elderly PD patients treated at The Second Rehabilitation Hospital of Shanghai between January 2023 and December 2024.Demographic and clinical data were obtained using standardized questionnaires.Anxiety,depression,and fatigue were assessed using the Beck Anxiety Inventory(BAI),Geriatric Depression Scale(GDS),and Fatigue Scale-14(FS-14),respectively.Binary logistic regression identified risk factors for anxiety and depression,whereas Spearman’s correlation assessed associations with fatigue.RESULTS Anxiety and depression prevalence rates were 64.2%(mean BAI score:19.59±10.92)and 56.1%(mean GDS score:12.82±6.37),respectively.The mean FS-14 total score was 9.46±1.89,comprising physical(5.77±1.51)and mental(3.69±1.20)fatigue components.Significant positive correlations were observed between fatigue scores(total,physical,and mental)and both anxiety and depression(all P<0.05).Univariate analysis revealed statistically significant associations between anxiety/depression and monthly income,disease duration,and disease severity(all P<0.05).Multivariate logistic regression indicated higher anxiety risk in patients with lower monthly income,prolonged disease duration,advanced disease severity,or multimorbidity.Depression risk was elevated in patients with lower monthly income and severe disease,whereas longer disease duration unexpectedly served as a protective factor.CONCLUSION Elderly PD patients show high rates of anxiety and depression,both of which are significantly correlated with fatigue severity.These findings highlight the importance of psychological monitoring and targeted mental health interventions in PD management among the elderly.展开更多
Cmyc,a proto-oncogene,is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells.However,recent studies suggest that Cmyc may play a crucial role in maintain...Cmyc,a proto-oncogene,is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells.However,recent studies suggest that Cmyc may play a crucial role in maintaining the health and function of mature dopaminergic neurons.This study assessed the role of Cmyc in dopaminergic neurons and its significance in Parkinson’s disease.We used a conditional knockout approach to specifically delete Cmyc in substantia nigra dopaminergic neurons of adult mice.Our findings showed that Cmyc deletion led to progressive neuron loss,Parkinson’s disease-like symptoms,downregulation of Klotho,and upregulation of senescence-associated inflammatory factors,along with enhanced oxidative stress and nitrated alpha-synuclein accumulation,ultimately causing neuronal death.In vitro experiments confirmed increased senescence in C-MYC knockout cells,which was partially reversible by KLOTHO overexpression.We conclude that low-level Cmyc expression is essential for maintaining the health of mature dopaminergic neurons and preventing neurodegeneration,and suggest the c-Myc/Klotho axis as a potential therapeutic target for age-related neurodegenerative diseases,including Parkinson’s disease.Our study introduces a novel mouse model for Parkinson’s disease that replicates a condition associated with normal aging,offering a valuable tool for future research into disease mechanisms and therapeutic strategies.展开更多
Background:Neurological disorders(NDs),including ischemic stroke(IS),Parkinson’s disease(PD),and Alzheimer’s disease(AD),are major contributors to global morbidity and mortality.Boswellia extract has demonstrated ne...Background:Neurological disorders(NDs),including ischemic stroke(IS),Parkinson’s disease(PD),and Alzheimer’s disease(AD),are major contributors to global morbidity and mortality.Boswellia extract has demonstrated neuroprotective properties,yet a comprehensive systematic review assessing its efficacy remains absent.This study aims to evaluate the efficacy of Boswellia extract in treating NDs,with a particular focus on its effects in AD and its potential for long-term neurorestoration,thereby supporting further investigation into Boswellia’s therapeutic role in ND management.Methods:A systematic literature search was performed in PubMed,Web of Science,ScienceDirect,and Google Scholar for English-language studies published up to March 2024.Eighteen studies met the inclusion criteria and were included in the meta-analysis.The study protocol was registered on PROSPERO(CRD42024524386).Eligible studies involved rodent models of IS,PD,or AD with post-operative interventions using Boswellia extract.Data extraction focused on mechanisms of action,dosages,treatment durations,and therapeutic outcomes.Studies were excluded if they involved non-ND models,combined treatments,or had incomplete data.Two researchers independently conducted literature screening and data extraction.Statistical analyses were conducted using Stata(version 17)and RevMan(version 5.4),employing fixed or random-effects models based on heterogeneity assessments.Result s:Boswellia extract significantly improved the mean effect size for NDs(ES=1.28,95%CI(1.05,1.51),P<0.001).Specifically,it reduced cerebral infarct volume in IS(SMD=−2.87,95%CI(−3.42,−2.32))and enhanced behavioral outcomes in AD(SMD=3.26,95%CI(2.07,5.14))and PD(SMD=5.37,95%CI(3.93,6.80)).Subgroup analyses revealed that Boswellia extract exhibited superior efficacy in AD when administered orally and via intra-cerebroventricular injection.Long-term treatment with Boswellia extract suggested potential neurorestorative effects.Additionally,Boswellia extract was more effective than its monomeric constituents,highlighting its promising role in ND treatment.Conclusion:Boswellia extract demonstrates significant neuroprotective effects across various NDs,particularly in AD and in promoting long-term neurorestoration.These findings support the need for further research into Boswellia’s potential as a therapeutic agent in the management of neurological disorders.展开更多
Myelination,the continuous ensheathment of neuronal axons,is a lifelong process in the nervous system that is essential for the precise,temporospatial conduction of action potentials between neurons.Myelin also provid...Myelination,the continuous ensheathment of neuronal axons,is a lifelong process in the nervous system that is essential for the precise,temporospatial conduction of action potentials between neurons.Myelin also provides intercellular metabolic support to axons.Even minor disruptions in the integrity of myelin can impair neural performance and increase susceptibility to neurological diseases.In fact,myelin degeneration is a well-known neuropathological condition that is associated with normal aging and several neurodegenerative diseases,including multiple sclerosis and Alzheimer’s disease.In the central nervous system,compact myelin sheaths are formed by fully mature oligodendrocytes.However,the entire oligodendrocyte lineage is susceptible to changes in the biological microenvironment and other risk factors that arise as the brain ages.In addition to their well-known role in action potential propagation,oligodendrocytes also provide intercellular metabolic support to axons by transferring energy metabolites and delivering exosomes.Therefore,myelin degeneration in the aging central nervous system is a significant contributor to the development of neurodegenerative diseases.Interventions that mitigate age-related myelin degeneration can improve neurological function in aging individuals.In this review,we investigate the changes in myelin that are associated with aging and their underlying mechanisms.We also discuss recent advances in understanding how myelin degeneration in the aging brain contributes to neurodegenerative diseases and explore the factors that can prevent,slow down,or even reverse age-related myelin degeneration.Future research will enhance our understanding of how reducing age-related myelin degeneration can be used as a therapeutic target for delaying or preventing neurodegenerative diseases.展开更多
Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patien...Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.展开更多
Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily...Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily involving abnormal development and damage of the dopaminergic system,pose significant public health challenges.Microglia,as the primary immune cells in the brain,are crucial in regulating neuronal circuit development and survival.From the embryonic stage to adulthood,microglia exhibit stage-specific gene expression profiles,transcriptome characteristics,and functional phenotypes,enhancing the susceptibility to early life stress.However,the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood.This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia,leading to dopaminergic system disorders,along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions.Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support(e.g.,insulin-like growth factor-1)and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning.Furthermore,blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission.Furthermore,inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons,inhibiting dopamine synthesis,reuptake,and receptor activity.Enhanced microglial phagocytosis inhibits dopamine axon extension.These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia.Indirectly,early life stress may influence microglial function through various pathways,such as astrocytic activation,the hypothalamic–pituitary–adrenal axis,the gut–brain axis,and maternal immune signaling.Finally,various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed.These strategies include classical antidepressants and antipsychotics,antibiotics and anti-inflammatory agents,and herbal-derived medicine.Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.展开更多
文摘Parkinsons disease(PD)is a chronic,progressive neurodegenerative disorder characterized by both motor and non-motor symptoms.Pain,a key component of PDs non-motor symptoms,was first documented by Charcot in 1872 as a potential correlate of the disease.While pharmacological and surgical interventions have gained traction in managing PD-related pain,the therapeutic framework remains inconsistent.Understanding the pathogenesis and contributing factors of PD pain is crucial for developing novel therapies and refining disease identification and treatment protocols.This review examines the potential mechanisms and influencing factors of PD-associated pain,with the aim of identifying new therapeutic targets for PD pain.
基金supported by the Spanish Ministry of Science and Innovation via a doctoral grant[FPU22/03656].supported by the Spanish Ministry of Science and Innovation(PID2022-137963OB-I00)Generalitat de Catalunya(2021-SGR-00635 AGAUR)+1 种基金CERCA Programme(Generalitat de Catalunya)by ICREA,ICREA-Academia 2020(to SV)。
文摘Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.
基金supported by Swiss Center for Applied Human Toxicology(SCAHT AP22-01)(to RN)。
文摘Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include disturbances in sleep,gastrointestinal function,and olfaction.PD misdiagnosis rates have been reported to reach approximately 30%,partly owing to the heterogeneity of parkinsonism with non-PD pathologies,and the differential diagnosis of PD from neurodegenerative diseases such as multiple systemic atrophy(MSA)and progressive supranuclear palsy poses another unmet need.
文摘Neurodegenerative diseases are a growing burden on healthcare systems.Patients with Alzheimer’s or Parkinson’s diseases(AD or PD)are desperately waiting for innovative solutions that are slow to come,despite several decades of research worldwide.In 2021 and again in 2023,two monoclonal antibodies,aducanumab and lecanemab,have been approved by the U.S.Food and Drug Administration,and a third,donanemab,is currently under review.However,these treatments have very limited efficacy on cognitive functions and are accompanied by major side effects:amyloid-related imaging abnormalities,microhemorrhages,and accelerated brain volume loss(Høilund-Carlsen et al.,2024).
基金supported by the DGIST start-up funds from the Ministry of Science and ICT(2024010330)a National Research Foundation of Korea(NRF)grant funded by the Korea Government(MSIT)(No.RS-2024-00351442)(to TWK).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).
基金supported by the Spanish Ministerio de Ciencia e Innovación/Agencia Española de Investigación(PID2021-124096OB-I00)(to JLV)JGR was granted by Demensfonden,The Royal Physiografic Society of Lund,Neurofonden,The Greta och Johan Kocks stiftelser,and Bertil och Ebon Norlins stiftelse.
文摘Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.
基金supported by the Swedish ResearchCouncil and the Swedish Brain Foundation,theCancer Research Funds of Radiumhemmet,theStrategic Research Area in Cancer(StratCan),the Strategic Research Area in Neuroscience(StratNeuro),the Swedish Cancer Society,theSwedish Childhood Cancer Foundation,theKarolinska Institutet Foundation,the InnoHKinitiative of the Innovation and TechnologyCommission of the Hong Kong SpecialAdministrative Region Government(to BJ).Openaccess funding is provided by the KarolinskaInstitute.
文摘In recent years,rising life expectancy has led to a significant increase in the prevalence of neurodegenerative disorders,including Alzheimer’s disease(AD),Parkinson’s disease,and age-related cognitive decline.Additionally,other neurological conditions such as glioblastoma,the most common and aggressive brain tumor in adults have been more frequently reported in aging populations.The brain itself is highly vulnerable to age-related changes,particularly disruptions in homeostatic regulation,which further contribute to its functional decline and heightened susceptibility to disease.This has led to a surge of interest in understanding the cellular and molecular mechanisms driving these changes.
文摘A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.
基金supported by grants from the Deutsche Forschungsgemeinschaft(HU 2614/1-1(Project No.462650276))the Fritz Thyssen Foundation(10.21.1.021MN)the Medical faculty of the University of Saarland(HOMFOR2016,HOMFORexzellent2017,HOMFOR2024 Anschubfinanzierung)to WH。
文摘Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Chronic wasting disease—a prion disease affecting cervids:Many neurological conditions,including Alzheimer's and Parkinson's diseases,amyotrophic lateral sclerosis,frontotemporal dementias,among others,are caused by the accumulation of misfolded proteins in the brain.These diseases affect not only humans,but also animals.
基金funded by the Russian Science Foundation(grant No.23-74-10092)(to AIS)。
文摘Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).
基金supported by ANR(ANR-21CE16-0008-01)ANR(ANR-21-CE16-0008-02 and ANR-23CE52-0007)+1 种基金UNADEV(A22018CS)(to HN)UNADEV(A22020CS)(to SB)。
文摘The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.
基金supported by the National Institute on Aging(Nos.AG000723 and AG000578)(to VAB)the Fondation Sante(No.19656),Greece 2.0+1 种基金the National Recovery and Resilience Plan’s flagship program TAEDR-0535850the European Research Council(No.101077374-Synapto Mitophagy)(to KP)。
文摘N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.
基金supported by the National Key R&D Program of China,No.2021YFC2501200(to PC).
文摘Short-chain fatty acids,metabolites produced by the fermentation of dietary fiber by gut microbiota,have garnered significant attention due to their correlation with neurodegenerative diseases,particularly Parkinson’s disease.In this review,we summarize the changes in short-chain fatty acid levels and the abundance of short-chain fatty acid-producing bacteria in various samples from patients with Parkinson’s disease,highlighting the critical role of gut homeostasis imbalance in the pathogenesis and progression of the disease.Focusing on the nervous system,we discuss the molecular mechanisms by which short-chain fatty acids influence the homeostasis of both the enteric nervous system and the central nervous system.We identify key processes,including the activation of G protein-coupled receptors and the inhibition of histone deacetylases by short-chain fatty acids.Importantly,structural or functional disruptions in the enteric nervous system mediated by these fatty acids may lead to abnormalα-synuclein expression and gastrointestinal dysmotility,which could serve as an initiating event in Parkinson’s disease.Furthermore,we propose that short-chain fatty acids help establish communication between the enteric nervous system and the central nervous system via the vagal nerve,immune circulation,and endocrine signaling.This communication may shed light on their potential role in the transmission ofα-synuclein from the gut to the brain.Finally,we elucidate novel treatment strategies for Parkinson’s disease that target short-chain fatty acids and examine the challenges associated with translating short-chain fatty acid-based therapies into clinical practice.In conclusion,this review emphasizes the pivotal role of short-chain fatty acids in regulating gut-brain axis integrity and their significance in the pathogenesis of Parkinson’s disease from the perspective of the nervous system.Moreover,it highlights the potential value of short-chain fatty acids in early intervention for Parkinson’s disease.Future research into the molecular mechanisms of short-chain fatty acids and their synergistic interactions with other gut metabolites is likely to advance the clinical translation of innovative short-chain fatty acid-based therapies for Parkinson’s disease.
基金Supported by Foundation of Shanghai Baoshan Science and Technology Commission,No.2024-E-66Shanghai Nursing Association Scientific Research Project,No.2024MS-B02.
文摘BACKGROUND Parkinson’s disease(PD)is a common neurodegenerative disorder in the elderly population.Non-motor symptoms such as anxiety and depression are often subtle,hindering early detection and intervention,yet they markedly affect quality of life and clinical outcomes.AIM To investigate the prevalence of anxiety and depression in elderly PD patients,identify associated risk factors,and assess their relationship with fatigue severity.METHODS A cross-sectional analysis was conducted in 123 elderly PD patients treated at The Second Rehabilitation Hospital of Shanghai between January 2023 and December 2024.Demographic and clinical data were obtained using standardized questionnaires.Anxiety,depression,and fatigue were assessed using the Beck Anxiety Inventory(BAI),Geriatric Depression Scale(GDS),and Fatigue Scale-14(FS-14),respectively.Binary logistic regression identified risk factors for anxiety and depression,whereas Spearman’s correlation assessed associations with fatigue.RESULTS Anxiety and depression prevalence rates were 64.2%(mean BAI score:19.59±10.92)and 56.1%(mean GDS score:12.82±6.37),respectively.The mean FS-14 total score was 9.46±1.89,comprising physical(5.77±1.51)and mental(3.69±1.20)fatigue components.Significant positive correlations were observed between fatigue scores(total,physical,and mental)and both anxiety and depression(all P<0.05).Univariate analysis revealed statistically significant associations between anxiety/depression and monthly income,disease duration,and disease severity(all P<0.05).Multivariate logistic regression indicated higher anxiety risk in patients with lower monthly income,prolonged disease duration,advanced disease severity,or multimorbidity.Depression risk was elevated in patients with lower monthly income and severe disease,whereas longer disease duration unexpectedly served as a protective factor.CONCLUSION Elderly PD patients show high rates of anxiety and depression,both of which are significantly correlated with fatigue severity.These findings highlight the importance of psychological monitoring and targeted mental health interventions in PD management among the elderly.
基金supported by the National Natural Science Foundation of China,No.81671263(to XX)Scientific Research and Innovation Team,Education Department of Anhui Province,China,No.2023AH010072(to XX)+1 种基金the Natural Science Foundation of Anhui Province,No.2208085MH221(to XX)The Key Projects for National Science Research of Education Department of Anhui Province,No.KJ2021A0851(to YD).
文摘Cmyc,a proto-oncogene,is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells.However,recent studies suggest that Cmyc may play a crucial role in maintaining the health and function of mature dopaminergic neurons.This study assessed the role of Cmyc in dopaminergic neurons and its significance in Parkinson’s disease.We used a conditional knockout approach to specifically delete Cmyc in substantia nigra dopaminergic neurons of adult mice.Our findings showed that Cmyc deletion led to progressive neuron loss,Parkinson’s disease-like symptoms,downregulation of Klotho,and upregulation of senescence-associated inflammatory factors,along with enhanced oxidative stress and nitrated alpha-synuclein accumulation,ultimately causing neuronal death.In vitro experiments confirmed increased senescence in C-MYC knockout cells,which was partially reversible by KLOTHO overexpression.We conclude that low-level Cmyc expression is essential for maintaining the health of mature dopaminergic neurons and preventing neurodegeneration,and suggest the c-Myc/Klotho axis as a potential therapeutic target for age-related neurodegenerative diseases,including Parkinson’s disease.Our study introduces a novel mouse model for Parkinson’s disease that replicates a condition associated with normal aging,offering a valuable tool for future research into disease mechanisms and therapeutic strategies.
基金supported by the National Natural Science Foundation of China,specifically through grants(No.8227431382304947)Key Research and Development Project of Shaanxi Province(2023GHZD43).Peer re v iew information。
文摘Background:Neurological disorders(NDs),including ischemic stroke(IS),Parkinson’s disease(PD),and Alzheimer’s disease(AD),are major contributors to global morbidity and mortality.Boswellia extract has demonstrated neuroprotective properties,yet a comprehensive systematic review assessing its efficacy remains absent.This study aims to evaluate the efficacy of Boswellia extract in treating NDs,with a particular focus on its effects in AD and its potential for long-term neurorestoration,thereby supporting further investigation into Boswellia’s therapeutic role in ND management.Methods:A systematic literature search was performed in PubMed,Web of Science,ScienceDirect,and Google Scholar for English-language studies published up to March 2024.Eighteen studies met the inclusion criteria and were included in the meta-analysis.The study protocol was registered on PROSPERO(CRD42024524386).Eligible studies involved rodent models of IS,PD,or AD with post-operative interventions using Boswellia extract.Data extraction focused on mechanisms of action,dosages,treatment durations,and therapeutic outcomes.Studies were excluded if they involved non-ND models,combined treatments,or had incomplete data.Two researchers independently conducted literature screening and data extraction.Statistical analyses were conducted using Stata(version 17)and RevMan(version 5.4),employing fixed or random-effects models based on heterogeneity assessments.Result s:Boswellia extract significantly improved the mean effect size for NDs(ES=1.28,95%CI(1.05,1.51),P<0.001).Specifically,it reduced cerebral infarct volume in IS(SMD=−2.87,95%CI(−3.42,−2.32))and enhanced behavioral outcomes in AD(SMD=3.26,95%CI(2.07,5.14))and PD(SMD=5.37,95%CI(3.93,6.80)).Subgroup analyses revealed that Boswellia extract exhibited superior efficacy in AD when administered orally and via intra-cerebroventricular injection.Long-term treatment with Boswellia extract suggested potential neurorestorative effects.Additionally,Boswellia extract was more effective than its monomeric constituents,highlighting its promising role in ND treatment.Conclusion:Boswellia extract demonstrates significant neuroprotective effects across various NDs,particularly in AD and in promoting long-term neurorestoration.These findings support the need for further research into Boswellia’s potential as a therapeutic agent in the management of neurological disorders.
基金supported by grants from Guangdong Basic and Applied Basic Research Foundation,No.2021A1515110801(to SW)the National Natural Science Foundation of China,No.82301511(to SW)+1 种基金“Double First-Class”Construction Project of NPU,Nos.0515023GH0202320(to JC),0515023SH0201320(to JC)973 Program,No.2011CB504100(to JC).
文摘Myelination,the continuous ensheathment of neuronal axons,is a lifelong process in the nervous system that is essential for the precise,temporospatial conduction of action potentials between neurons.Myelin also provides intercellular metabolic support to axons.Even minor disruptions in the integrity of myelin can impair neural performance and increase susceptibility to neurological diseases.In fact,myelin degeneration is a well-known neuropathological condition that is associated with normal aging and several neurodegenerative diseases,including multiple sclerosis and Alzheimer’s disease.In the central nervous system,compact myelin sheaths are formed by fully mature oligodendrocytes.However,the entire oligodendrocyte lineage is susceptible to changes in the biological microenvironment and other risk factors that arise as the brain ages.In addition to their well-known role in action potential propagation,oligodendrocytes also provide intercellular metabolic support to axons by transferring energy metabolites and delivering exosomes.Therefore,myelin degeneration in the aging central nervous system is a significant contributor to the development of neurodegenerative diseases.Interventions that mitigate age-related myelin degeneration can improve neurological function in aging individuals.In this review,we investigate the changes in myelin that are associated with aging and their underlying mechanisms.We also discuss recent advances in understanding how myelin degeneration in the aging brain contributes to neurodegenerative diseases and explore the factors that can prevent,slow down,or even reverse age-related myelin degeneration.Future research will enhance our understanding of how reducing age-related myelin degeneration can be used as a therapeutic target for delaying or preventing neurodegenerative diseases.
基金supported by the Canadian Institutes of Health Research(DFD-181599)the National Institutes of Health(T32AG058527)to RJB and R0190106435 to VM.
文摘Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.
基金supported by the National Natural Science Foundation of China,Nos.82304990(to NY),81973748(to JC),82174278(to JC)the National Key R&D Program of China,No.2023YFE0209500(to JC)+4 种基金China Postdoctoral Science Foundation,No.2023M732380(to NY)Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine,No.202102010014(to JC)Huang Zhendong Research Fund for Traditional Chinese Medicine of Jinan University,No.201911(to JC)National Innovation and Entrepreneurship Training Program for Undergraduates in China,No.202310559128(to NY and QM)Innovation and Entrepreneurship Training Program for Undergraduates at Jinan University,Nos.CX24380,CX24381(both to NY and QM)。
文摘Early life stress correlates with a higher prevalence of neurological disorders,including autism,attention-deficit/hyperactivity disorder,schizophrenia,depression,and Parkinson's disease.These conditions,primarily involving abnormal development and damage of the dopaminergic system,pose significant public health challenges.Microglia,as the primary immune cells in the brain,are crucial in regulating neuronal circuit development and survival.From the embryonic stage to adulthood,microglia exhibit stage-specific gene expression profiles,transcriptome characteristics,and functional phenotypes,enhancing the susceptibility to early life stress.However,the role of microglia in mediating dopaminergic system disorders under early life stress conditions remains poorly understood.This review presents an up-to-date overview of preclinical studies elucidating the impact of early life stress on microglia,leading to dopaminergic system disorders,along with the underlying mechanisms and therapeutic potential for neurodegenerative and neurodevelopmental conditions.Impaired microglial activity damages dopaminergic neurons by diminishing neurotrophic support(e.g.,insulin-like growth factor-1)and hinders dopaminergic axon growth through defective phagocytosis and synaptic pruning.Furthermore,blunted microglial immunoreactivity suppresses striatal dopaminergic circuit development and reduces neuronal transmission.Furthermore,inflammation and oxidative stress induced by activated microglia can directly damage dopaminergic neurons,inhibiting dopamine synthesis,reuptake,and receptor activity.Enhanced microglial phagocytosis inhibits dopamine axon extension.These long-lasting effects of microglial perturbations may be driven by early life stress–induced epigenetic reprogramming of microglia.Indirectly,early life stress may influence microglial function through various pathways,such as astrocytic activation,the hypothalamic–pituitary–adrenal axis,the gut–brain axis,and maternal immune signaling.Finally,various therapeutic strategies and molecular mechanisms for targeting microglia to restore the dopaminergic system were summarized and discussed.These strategies include classical antidepressants and antipsychotics,antibiotics and anti-inflammatory agents,and herbal-derived medicine.Further investigations combining pharmacological interventions and genetic strategies are essential to elucidate the causal role of microglial phenotypic and functional perturbations in the dopaminergic system disrupted by early life stress.
