Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,includin...Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis.Indeed,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS conditions.In such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy.Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system.This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.展开更多
Our common home,planet Earth,is inhabited by more than 7 billion human beings.The average life expectancy currently estimated for men is^69 years,with strong differences among countries.Currently,neurodegenerative dis...Our common home,planet Earth,is inhabited by more than 7 billion human beings.The average life expectancy currently estimated for men is^69 years,with strong differences among countries.Currently,neurodegenerative diseases are currently the leading cause of death and disability worldwide.In clinical use and neuroscience research,a solution for an effective diagnosis is in progress,but a prophylactic treatment to counteract this long-lasting plague for humanity is still unidentified.展开更多
Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to r...Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.展开更多
Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is ...Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins,its closest homolog being the fungal ERG2 sterol isomerase.Even its pharmacological counterpart,the Sigma-2 receptor that was only recently cloned,is genetically distinct.S1R is more likely considered as an atypical ligand-modulated chaperone protein.S1R is widely expressed in many organs including brain where its function has mainly been explored.展开更多
Harmful and helpful roles of astrocytes in spinal cord injury(SCI):SCI induce gradable sensory,motor and autonomic impairments that correlate with the lesion severity and the rostro-caudal location of the injury site....Harmful and helpful roles of astrocytes in spinal cord injury(SCI):SCI induce gradable sensory,motor and autonomic impairments that correlate with the lesion severity and the rostro-caudal location of the injury site.The absence of spontaneous axonal regeneration after injury results from neuron-intrinsic and neuron-extrinsic parameters.Indeed,not only adult neurons display limited capability to regrow axons but also the injury environment contains inhibitors to axonal regeneration and a lack of growth-promoting factors.Amongst other cell populations that respond to the lesion,reactive astrocytes were first considered as only detrimental to spontaneous axonal regeneration.Indeed,astrocytes.展开更多
Background Amyotrophic lateral sclerosis(ALS)is characterised by degeneration of motor neurons,leading to muscle weakness and progressive paralysis.Currently,no treatment is available to halt or reverse the progressio...Background Amyotrophic lateral sclerosis(ALS)is characterised by degeneration of motor neurons,leading to muscle weakness and progressive paralysis.Currently,no treatment is available to halt or reverse the progression of the disease.Oxidative stress,mitochondrial dysfunction,accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS.A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death.Targeting sigma-1 receptor(S1R)could meet this objective,as this chaperone protein modulates many cell survival mechanisms.So far,the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2%of patients.In the present study,the impact of two different S1R activators,the reference agonist PRE-084 and the positive modulator OZP002,was compared on two key ALS genes:TDP43 and C9orf72.Methods The dissociation of S1R from Binding immunoglobulin Protein(BiP)was determined using ELISA.OZP002 toxicity was compared to PRE-084 on zebrafish larvae with increasing concentrations.The efficacy of OZP002 and PRE-084 was evaluated on the locomotor escape response of zebrafish expressing mutant TDP43 or one C9orf72 toxic dipeptide.Their effects on NRF2 target gene expression were studied by qPCR.The beneficial effect was further examined on the locomotor performances of TDP43A315T mice using rotarod and beam walking tests.We also performed analysis on motor neuron loss and glial reactivity.Results OZP002 is a positive modulator of S1R,that increases the dissociation of the S1R-BiP complex induced by orthosteric agonists.S1R activation by both OZP002 and PRE-084 restored the locomotor response of ALS zebrafish expressing either TDP43 or one C9orf72 toxic dipeptide.The neuroprotection was due at least in part to the NRF2 cascade stimulation but not with a direct interaction.More importantly,OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43A315T transgenic mice.Astroglial and microglial reactivities were also reduced by both activators.Conclusions We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology.Additionally,we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.展开更多
The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to for...The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to form thermodynamically stable complexes with Aβspecies,peptides and fibrils.As the drug showed a chemical scaffold coherent for an effective interaction with theσ_(1) receptor chaperone and asσ_(1) agonists are currently developed as potent neuroprotectants in AD,we investigated the pharmacological action of Amylovis-201 on theσ_(1) receptor.We report that Amylovis-201 is a potentσ_(1) agonist by several in silico,in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action atσ_(1) receptors.Furthermore,we show for the first time that classicalσ_(1) receptor agonist(PRE-084),and antagonist(NE-100)are able to interact and disaggregate Aβ_(25-35) fibrils.Interestingly,Amylovis-201 was the only compound inhibiting Aβ_(25-35) aggregates formation.Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent andσ_(1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.展开更多
文摘Amyotrophic lateral sclerosis（ALS）is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis.Indeed,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS conditions.In such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy.Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system.This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.
文摘Our common home,planet Earth,is inhabited by more than 7 billion human beings.The average life expectancy currently estimated for men is^69 years,with strong differences among countries.Currently,neurodegenerative diseases are currently the leading cause of death and disability worldwide.In clinical use and neuroscience research,a solution for an effective diagnosis is in progress,but a prophylactic treatment to counteract this long-lasting plague for humanity is still unidentified.
基金supported by a grant from the Association Française contre les Myopathies(AFM Téléthongrant 23667,to JCL).
文摘Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.
文摘Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins,its closest homolog being the fungal ERG2 sterol isomerase.Even its pharmacological counterpart,the Sigma-2 receptor that was only recently cloned,is genetically distinct.S1R is more likely considered as an atypical ligand-modulated chaperone protein.S1R is widely expressed in many organs including brain where its function has mainly been explored.
基金supported by the patient organizations“Verticale”(to YNG and FEP).
文摘Harmful and helpful roles of astrocytes in spinal cord injury(SCI):SCI induce gradable sensory,motor and autonomic impairments that correlate with the lesion severity and the rostro-caudal location of the injury site.The absence of spontaneous axonal regeneration after injury results from neuron-intrinsic and neuron-extrinsic parameters.Indeed,not only adult neurons display limited capability to regrow axons but also the injury environment contains inhibitors to axonal regeneration and a lack of growth-promoting factors.Amongst other cell populations that respond to the lesion,reactive astrocytes were first considered as only detrimental to spontaneous axonal regeneration.Indeed,astrocytes.
基金supported by a grant from the Association Francaise contre les Myopathies(AFM Telethon,grant 23667).
文摘Background Amyotrophic lateral sclerosis(ALS)is characterised by degeneration of motor neurons,leading to muscle weakness and progressive paralysis.Currently,no treatment is available to halt or reverse the progression of the disease.Oxidative stress,mitochondrial dysfunction,accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS.A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death.Targeting sigma-1 receptor(S1R)could meet this objective,as this chaperone protein modulates many cell survival mechanisms.So far,the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2%of patients.In the present study,the impact of two different S1R activators,the reference agonist PRE-084 and the positive modulator OZP002,was compared on two key ALS genes:TDP43 and C9orf72.Methods The dissociation of S1R from Binding immunoglobulin Protein(BiP)was determined using ELISA.OZP002 toxicity was compared to PRE-084 on zebrafish larvae with increasing concentrations.The efficacy of OZP002 and PRE-084 was evaluated on the locomotor escape response of zebrafish expressing mutant TDP43 or one C9orf72 toxic dipeptide.Their effects on NRF2 target gene expression were studied by qPCR.The beneficial effect was further examined on the locomotor performances of TDP43A315T mice using rotarod and beam walking tests.We also performed analysis on motor neuron loss and glial reactivity.Results OZP002 is a positive modulator of S1R,that increases the dissociation of the S1R-BiP complex induced by orthosteric agonists.S1R activation by both OZP002 and PRE-084 restored the locomotor response of ALS zebrafish expressing either TDP43 or one C9orf72 toxic dipeptide.The neuroprotection was due at least in part to the NRF2 cascade stimulation but not with a direct interaction.More importantly,OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43A315T transgenic mice.Astroglial and microglial reactivities were also reduced by both activators.Conclusions We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology.Additionally,we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.
基金supported by a PHC Carlos J.Finlay program from Campus France(project 47069SA)to TM and CRT.
文摘The aggregation of Amyloid-β(Aβ)peptides is associated with neurodegeneration in Alzheimer's disease(AD).We previously identified novel naphtalene derivatives,including the lead compound Amylovis-201,able to form thermodynamically stable complexes with Aβspecies,peptides and fibrils.As the drug showed a chemical scaffold coherent for an effective interaction with theσ_(1) receptor chaperone and asσ_(1) agonists are currently developed as potent neuroprotectants in AD,we investigated the pharmacological action of Amylovis-201 on theσ_(1) receptor.We report that Amylovis-201 is a potentσ_(1) agonist by several in silico,in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action atσ_(1) receptors.Furthermore,we show for the first time that classicalσ_(1) receptor agonist(PRE-084),and antagonist(NE-100)are able to interact and disaggregate Aβ_(25-35) fibrils.Interestingly,Amylovis-201 was the only compound inhibiting Aβ_(25-35) aggregates formation.Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent andσ_(1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.
