NRF2 signaling cascade in amyotrophic lateral sclerosis:bridging the gap between promise and reality

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.

In vivo astrocyte reprogramming following spinal cord injury

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.

Mitochondrial quality control in amyotrophic lateral sclerosis：towards a common pathway？

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.

Sigma-1 receptor: culprit and rescuer in motor neuron diseases

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.

Neuroprotective effect of Neuro-EPO in neurodegenerative diseases:“Alea jacta est”

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.

Amylovis-201 is a new dual-target ligand,acting as an anti-amyloidogenic compound and a potent agonist of theσ1 chaperone protein

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.