Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor...Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.展开更多
“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging...“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.展开更多
Autophagy is a cellular degradation and recycling system,indispensable for cellular and organ development,homeostasis,and function.This cellular process is evolutionarily highly conserved to quality control of many pr...Autophagy is a cellular degradation and recycling system,indispensable for cellular and organ development,homeostasis,and function.This cellular process is evolutionarily highly conserved to quality control of many proteins and dysfunctional organelles,which finally recycle components as amino acids.This process is effective during normal physiology as part of anabolism and plays an additional important role during starvation(Dikic and Elazar,2018).Different types of autophagy have been chara cterized based on their dynamic,mechanism of action,target substrates,and protein markers.Some of them are macroautophagy(hereafter called"autophagy"),microa utophagy,and chape rone-media ted autophagy(Fleming et al.,2022).展开更多
Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamin...Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.展开更多
Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and...Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.展开更多
In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,pla...In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,plasticity,oxidative stress and neuroinflammation.Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide.Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms.Today,there are no available curative or disease modifying treatments for Parkinson’s disease,but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease,both in diabetic and nondiabetic Parkinsonian patients.Furthermore,it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease.Here,we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism,with a particular focus on glucagon-like peptide-1 receptor agonists.展开更多
Peripheral nerve injuries caused by accidents may lead to paralysis,sensory disturbances,anaesthesia,and lack of autonomic functions.Functional recovery after disconnection of the motoneuronal soma from target tissue ...Peripheral nerve injuries caused by accidents may lead to paralysis,sensory disturbances,anaesthesia,and lack of autonomic functions.Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors:motoneuronal soma viability,proper axonal sprouting across inhibitory zones and elongation toward specific muscle,effective synapse contact rebuilding,and prevention of muscle atrophy.Therapies,such as adjuvant drugs with pleiotropic effects,that promote functional recovery after peripheral nerve injury are needed.Toward this aim,we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools.Our focus is on boosting intrinsic capabilities of neurons for neuroprotection;this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition.Using our workflow,we discovered neuroheal,a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection,is anti-inflammatory,enhances axonal regeneration after axotomy,and reduces muscle atrophy.This drug discovery workflow has thus yielded a therapy that is close to its clinical application.展开更多
Acetylation is a post-translational modification that is regulated by two antagonistic enzymes,histone acetyltransferases(HATs)and histone deacetylases(HDACs).HATs transfer the acetyl group from acetyl-CoA to lysine r...Acetylation is a post-translational modification that is regulated by two antagonistic enzymes,histone acetyltransferases(HATs)and histone deacetylases(HDACs).HATs transfer the acetyl group from acetyl-CoA to lysine residues of proteins while HDACs remove it(Yakhine-Diop et al.,2018b).The impairment of HAT or HDAC activity elicits changes in the protein acetylation status which disturb several cellular processes,among others,gene expression,autophagy etc.,leading finally to cell death.Both enzymes are associated with Parkinson’s disease(PD)pathogenesis.In dopaminergic cells,neurotoxins provoke apoptotic cell death by increasing histone acetylation levels.While paraquat(Song et al.,2011)and rotenone(Feng et al.,2015)reduce HDAC activity,dieldrin(Song et al.,2010)enhances HAT activity.However in vivo,paraquat-induced upregulation ofα-synuclein triggers histone hypoacetylation.展开更多
Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induce...Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy（OIN） is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes： acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309（previously developed as E-52862） is a novel selective sigma-1 receptor（S1R） antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase Ⅱ, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer（CRC） treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular ...Alzheimer’s disease(AD)is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein.Over the years,AD has been classified in two subgroups:early onset or familial AD and late onset or sporadic AD.On the one hand,familial AD has been described to be the result of genetic mutations that cause,in some cases,for the overproduction of amyloid β.On the other,the cause of late onset or sporadic AD is still unclear even though several hypotheses have been proposed to explain the process of severe and progressive memory and cognitive loss.In the present review,some of the current hypotheses that try to explain the origin of late onset or sporadic AD have been summarized.Also,their potential implication in the development of new drugs for the presymptomatic treatment of late onset or sporadic AD has been considered.展开更多
Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generat...Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.展开更多
Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related t...Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related to mutations in causative genes, while the vast majority of amyotrophic lateral sclerosis cases are considered to be sporadic, resulting from the interaction between genes and environmental factors in predisposed individuals. During the past few years, dozens of drugs have been postulated as promising strategies for the disease after showing some beneficial effects in preclinical cellular and murine models. However, the translation into clinical practice has been largely unsuccessful and the compounds failed when were tested in clinical trials. This might be explained, at least partially, by the enormous complexity of the disease both from clinico-epidemiological and a pathogenic points of view. In this review, we will briefly comment on the complexity of the disease focusing on some recent findings, and we will suggest how amyotrophic lateral sclerosis research might be reoriented to foster the advance in the diagnostic and therapeutic questions.展开更多
Alzheimer's disease(AD) is the widespread and the most feared neurodegenerative disorder leading to dementia in the elderly.ADy by eliminating intelligence,diminishes a man to helpless body,places an unbearable st...Alzheimer's disease(AD) is the widespread and the most feared neurodegenerative disorder leading to dementia in the elderly.ADy by eliminating intelligence,diminishes a man to helpless body,places an unbearable strain on patients,families,and fuels socioeconomic healthcare crises around the world.The main histopathological hallmarks of AD are the accumulation of extracellular amyloid depositions known as senile plaques and intracellular neurofibrillary to ngles,together with severe dysfunctional synaptic connectivity and neuronal death leading to brain atrophy.展开更多
Upon activation, tumor necrosis factor alpha （TNF-α） receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believ...Upon activation, tumor necrosis factor alpha （TNF-α） receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D （ActD） become susceptible to TNF-α-induced cell death through the activation of caspase-8, generation of tBid and activation of caspase-9 and -3. Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-XL protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ ActD treatments. Moreover, Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-XL are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation. Altogether, our results demonstrate that Bcl-XL, and not Bci-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-κB-independent manner.展开更多
The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centere...The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.展开更多
Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypot...Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.展开更多
Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary fo...Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor （NSF） Attachment Protein Receptor （SNARE） proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration.展开更多
Lactoferrin is an antimicrobial prote in characterized by the exertion of many protective functions,including antibacterial,antifungal,antiviral,and antiparasitic properties,as well as anti-inflammatory and immunomodu...Lactoferrin is an antimicrobial prote in characterized by the exertion of many protective functions,including antibacterial,antifungal,antiviral,and antiparasitic properties,as well as anti-inflammatory and immunomodulatory activities(Kruzel et al.,2017).Lactoferrin is one of the major proteins present in exocrine secretions,including saliva,and is therefore associated with host defense against oral pathogens and control of the oral microbiome.In recent years,it has become clear that alterations in the oral microbiome may contribute to opportunistic pathogen infections in the brains of Alzheimer’s disease(AD)patients and thus participate in or contribute to the development of this neurodegenerative disease(Sureda et al.,2020).Pathogenic oral microbes can affect neurological processes by entering brain tissue through various pathways and directly damaging the central nervous system.In the central nervous system,oral microbes may trigger an immune response that increases amyloidβ(Aβ)production and may even trigger the Aβcascade to promote the onset of AD,as we discuss in our previous study supporting the“infectious hypothesis”in AD(González-Sánchez et al.,2020).展开更多
Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the ...Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.展开更多
文摘Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.
文摘“Last scene of all that ends this strange,eventful history,is second childishness and mere oblivion.I am sans teeth,sans eyes,sans taste,sans everything.”William Shakespeare‘As You Like It'Act 2,Sc.7,l.139Aging of the human brain is characterized by a progressive decline of its functional capacity;this decline however varies widely,and cognitive longevity differs substantially between individuals.
基金supported by Grants from Spanish FEDER/Science and Innovation Ministry I+D+i-RETOS-PID2021-124801NB-100Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas(CIBERN ED+1 种基金an initiative of the ISCIII)[PI2016/01]the Fundocion Ramon Areces and Banco Santander to the CBMSO(to FW)。
文摘Autophagy is a cellular degradation and recycling system,indispensable for cellular and organ development,homeostasis,and function.This cellular process is evolutionarily highly conserved to quality control of many proteins and dysfunctional organelles,which finally recycle components as amino acids.This process is effective during normal physiology as part of anabolism and plays an additional important role during starvation(Dikic and Elazar,2018).Different types of autophagy have been chara cterized based on their dynamic,mechanism of action,target substrates,and protein markers.Some of them are macroautophagy(hereafter called"autophagy"),microa utophagy,and chape rone-media ted autophagy(Fleming et al.,2022).
基金supported by grants from Consellería de Cultura,Educación e Ordenación Universitaria,Xunta de Galicia(ED431G/05,ED431C 2018/10)European Regional Development Fund(FEDER),Instituto de Salud CarlosⅢ(RD16/011/0016,RD21/0017/0031)Secretaría de Estado de Investigación,Desarrollo e Innovación(Grant/Award,number RTI2018-098830-B-I00)(to JLLG)。
文摘Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.
文摘Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.
基金supported by the Spanish Ministry of Health(PI17/00828 and Ciberned)Galician Government(XUGA,ED431C 2018/10,ED431G/05)FEDER(Regional European Development Fund),all to AIRP.
文摘In the last decade,attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system,as insulin in the brain is implicated in neuronal survival,plasticity,oxidative stress and neuroinflammation.Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide.Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms.Today,there are no available curative or disease modifying treatments for Parkinson’s disease,but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease,both in diabetic and nondiabetic Parkinsonian patients.Furthermore,it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease.Here,we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism,with a particular focus on glucagon-like peptide-1 receptor agonists.
基金mainly supported by the Ministerio de Economíay Competitividad of Spain(#SAF 2014-59701)(to CC)
文摘Peripheral nerve injuries caused by accidents may lead to paralysis,sensory disturbances,anaesthesia,and lack of autonomic functions.Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors:motoneuronal soma viability,proper axonal sprouting across inhibitory zones and elongation toward specific muscle,effective synapse contact rebuilding,and prevention of muscle atrophy.Therapies,such as adjuvant drugs with pleiotropic effects,that promote functional recovery after peripheral nerve injury are needed.Toward this aim,we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools.Our focus is on boosting intrinsic capabilities of neurons for neuroprotection;this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition.Using our workflow,we discovered neuroheal,a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection,is anti-inflammatory,enhances axonal regeneration after axotomy,and reduces muscle atrophy.This drug discovery workflow has thus yielded a therapy that is close to its clinical application.
文摘Acetylation is a post-translational modification that is regulated by two antagonistic enzymes,histone acetyltransferases(HATs)and histone deacetylases(HDACs).HATs transfer the acetyl group from acetyl-CoA to lysine residues of proteins while HDACs remove it(Yakhine-Diop et al.,2018b).The impairment of HAT or HDAC activity elicits changes in the protein acetylation status which disturb several cellular processes,among others,gene expression,autophagy etc.,leading finally to cell death.Both enzymes are associated with Parkinson’s disease(PD)pathogenesis.In dopaminergic cells,neurotoxins provoke apoptotic cell death by increasing histone acetylation levels.While paraquat(Song et al.,2011)and rotenone(Feng et al.,2015)reduce HDAC activity,dieldrin(Song et al.,2010)enhances HAT activity.However in vivo,paraquat-induced upregulation ofα-synuclein triggers histone hypoacetylation.
文摘Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy（OIN） is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes： acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309（previously developed as E-52862） is a novel selective sigma-1 receptor（S1R） antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase Ⅱ, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer（CRC） treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.
基金supported by the Spanish Ministry of Science and Innovation SAF2017-84283-R,PI2016/01,CB06/05/0024(Biomedical Research Networking Centre in Neurodegenerative Diseases)the European Regional Development Founds(all to AC)
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disease that was histopathologically characterized in the brain by the presence of extracellular senile plaques made of amyloid β peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein.Over the years,AD has been classified in two subgroups:early onset or familial AD and late onset or sporadic AD.On the one hand,familial AD has been described to be the result of genetic mutations that cause,in some cases,for the overproduction of amyloid β.On the other,the cause of late onset or sporadic AD is still unclear even though several hypotheses have been proposed to explain the process of severe and progressive memory and cognitive loss.In the present review,some of the current hypotheses that try to explain the origin of late onset or sporadic AD have been summarized.Also,their potential implication in the development of new drugs for the presymptomatic treatment of late onset or sporadic AD has been considered.
基金supported by NIH Grant Al-15614 (to CAD)the Ministerio de Ciencia e Innovacion (PID2020-120267BRI00AEI/10.13039/501100011033)(to RLV)。
文摘Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.
文摘Amyotrophic lateral sclerosis, the most common neurodegenerative disease affecting motor neurons, lacks an effective treatment. A small fraction of amyotrophic lateral sclerosis cases have a familial origin, related to mutations in causative genes, while the vast majority of amyotrophic lateral sclerosis cases are considered to be sporadic, resulting from the interaction between genes and environmental factors in predisposed individuals. During the past few years, dozens of drugs have been postulated as promising strategies for the disease after showing some beneficial effects in preclinical cellular and murine models. However, the translation into clinical practice has been largely unsuccessful and the compounds failed when were tested in clinical trials. This might be explained, at least partially, by the enormous complexity of the disease both from clinico-epidemiological and a pathogenic points of view. In this review, we will briefly comment on the complexity of the disease focusing on some recent findings, and we will suggest how amyotrophic lateral sclerosis research might be reoriented to foster the advance in the diagnostic and therapeutic questions.
基金supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,grant No.27724/2018-2)Coordenacao de Aperfeicoamento de Pessoal de Nível Superior(CAPES,grant No.88887.2005.00/2018-00)。
文摘Alzheimer's disease(AD) is the widespread and the most feared neurodegenerative disorder leading to dementia in the elderly.ADy by eliminating intelligence,diminishes a man to helpless body,places an unbearable strain on patients,families,and fuels socioeconomic healthcare crises around the world.The main histopathological hallmarks of AD are the accumulation of extracellular amyloid depositions known as senile plaques and intracellular neurofibrillary to ngles,together with severe dysfunctional synaptic connectivity and neuronal death leading to brain atrophy.
文摘Upon activation, tumor necrosis factor alpha （TNF-α） receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D （ActD） become susceptible to TNF-α-induced cell death through the activation of caspase-8, generation of tBid and activation of caspase-9 and -3. Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-XL protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ ActD treatments. Moreover, Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-XL are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation. Altogether, our results demonstrate that Bcl-XL, and not Bci-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-κB-independent manner.
文摘The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms,particularly DNA methylation.This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology.The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression.The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus.Notably,ANK1 hypermethylation,a protein implicated in neurofibrillary tangle formation,was recurrently identified in the entorhinal cortex.Further,the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3,RHBDF2,and MCF2L,potentially influencing neuroinflammatory processes.The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns.Despite the disparities across studies,these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology.Future research efforts should address methodological variations,incorporate diverse cohorts,and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression.
文摘Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.
基金supported by the Ramon y Cajal programme(RYC-2007-00417,RYC-2009-05510)grants from the Spanish MINECO(SAF2013-42445R and BFU2010-21507)CIBERNED
文摘Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor （NSF） Attachment Protein Receptor （SNARE） proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration.
文摘Lactoferrin is an antimicrobial prote in characterized by the exertion of many protective functions,including antibacterial,antifungal,antiviral,and antiparasitic properties,as well as anti-inflammatory and immunomodulatory activities(Kruzel et al.,2017).Lactoferrin is one of the major proteins present in exocrine secretions,including saliva,and is therefore associated with host defense against oral pathogens and control of the oral microbiome.In recent years,it has become clear that alterations in the oral microbiome may contribute to opportunistic pathogen infections in the brains of Alzheimer’s disease(AD)patients and thus participate in or contribute to the development of this neurodegenerative disease(Sureda et al.,2020).Pathogenic oral microbes can affect neurological processes by entering brain tissue through various pathways and directly damaging the central nervous system.In the central nervous system,oral microbes may trigger an immune response that increases amyloidβ(Aβ)production and may even trigger the Aβcascade to promote the onset of AD,as we discuss in our previous study supporting the“infectious hypothesis”in AD(González-Sánchez et al.,2020).
基金funded by the Spanish Ministry of Health-Instituto Carlos Ⅲ(Miguel Servet programme-CP/00041) to FL
文摘Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.
