Selective Vulnerability of Neuronal Subtypes in ALS: A Fertile Ground for the Identification of Therapeutic Targets

It is well defined that subpopulations of motoneurons have different vulnerability to the pathology causing amyotrophic lateral sclerosis (ALS). In the spinal cord, the fast fatigable motoneurons have been shown to be the first to degenerate, followed by fatigue-resistant and slow motoneurons. In contrast motoneurons located in the Onuf’s and oculomotor nuclei appear to be resistant to disease. With a focus on research mainly done on mice overexpressing the mutated human superoxide dismutase (SOD1) protein, we review recent studies exploring the mechanisms that underlie the selective vulnerability of the various motoneuron subtypes. By comparing differences in gene expression between these populations, it has been possible to identify factors, which critically determine the survival of motoneurons and the neuromuscular function in the pathologic context of ALS. Furthermore, we discuss the contribution of non-cell autonomous processes, involving glial cells and the skeletal muscle, in the neurodegenerative process. Exploring the cause of neurodegeneration from the angle of the selective neuronal vulnerability has recently led to the identification of novel targets, which open opportunities for therapeutic intervention against ALS

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration

Mutations in SIGMAR1, which encodes the Sigma 1 receptor, cause a familial form of amyotrophic lateral sclerosis, but the underlying molecular mechanisms are unclear. Bernard-Marissal et al. reveal that disruption of Sigma 1 receptor function disturbs endoplasmic reticulum-mitochondria interactions and functions, resulting in degeneration specifically of motor neuron

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.

Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases

Le logement à Bruxelles : diagnostic et enjeux

Cette note de synthèse met en lumière, en variant les approches (démographiques, juridiques, politiques, sociologiques), les diverses facettes de la problématique du logement à Bruxelles. Elle ne constitue pas un état des savoirs exhaustif sur l’habitat, mais offre un panorama des connaissances et des enjeux actuels. Elle met en évidence les différentes dimensions du logement dans le contexte de la croissance démographique et de la fragmentation sociale, révèle les controverses et débats à son sujet et pointe les principaux enjeux pour le futur.Deze synthesenota verduidelijkt de verschillende aspecten van de huidige huisvestingsproblematiek in Brussel vanuit verschillende invalshoeken (demografisch, juridisch, politiek en sociologisch). De nota verstrekt geen exhaustieve stand van zaken van de kennis over de woonomgeving, maar biedt een overzicht van de huidige kennis en actuele uitdagingen. De nota licht de verschillende dimensies van de huisvestingsproblematiek toe in de context van de demografische groei en de sociale fragmentering, brengt de controverses en debatten over dat vraagstuk aan het licht en stipt de grootste uitdagingen voor de toekomst aan.This synopsis highlights the various facets of the housing problem in Brussels through different approaches (demographic, legal, political and sociological). It does not constitute an exhaustive state of knowledge regarding housing, but presents a panorama of current knowledge and challenges. It highlights the different dimensions of housing in the context of demographic growth and social fragmentation, reveals the controversies and debates on this subject and points out the main challenges for the future

Huisvesting in Brussel: diagnose en uitdagingen

Deze synthesenota verduidelijkt de verschillende aspecten van de huidige huisvestingsproblematiek in Brussel vanuit verschillende invalshoeken (demografisch, juridisch, politiek en sociologisch). De nota verstrekt geen exhaustieve stand van zaken van de kennis over de woonomgeving, maar biedt een overzicht van de huidige kennis en actuele uitdagingen. De nota licht de verschillende dimensies van de huisvestingsproblematiek toe in de context van de demografische groei en de sociale fragmentering, brengt de controverses en debatten over dat vraagstuk aan het licht en stipt de grootste uitdagingen voor de toekomst aan.Cette note de synthèse met en lumière, en variant les approches (démographiques, juridiques, politiques, sociologiques), les diverses facettes de la problématique du logement à Bruxelles. Elle ne constitue pas un état des savoirs exhaustif sur l’habitat, mais offre un panorama des connaissances et des enjeux actuels. Elle met en évidence les différentes dimensions du logement dans le contexte de la croissance démographique et de la fragmentation sociale, révèle les controverses et débats à son sujet et pointe les principaux enjeux pour le futur.This synopsis highlights the various facets of the housing problem in Brussels through different approaches (demographic, legal, political and sociological). It does not constitute an exhaustive state of knowledge regarding housing, but presents a panorama of current knowledge and challenges. It highlights the different dimensions of housing in the context of demographic growth and social fragmentation, reveals the controversies and debates on this subject and points out the main challenges for the future

Housing in Brussels: diagnosis and challenges

This synopsis highlights the various facets of the housing problem in Brussels through different approaches (demographic, legal, political and sociological). It does not constitute an exhaustive state of knowledge regarding housing, but presents a panorama of current knowledge and challenges. It highlights the different dimensions of housing in the context of demographic growth and social fragmentation, reveals the controversies and debates on this subject and points out the main challenges for the future.Cette note de synthèse met en lumière, en variant les approches (démographiques, juridiques, politiques, sociologiques), les diverses facettes de la problématique du logement à Bruxelles. Elle ne constitue pas un état des savoirs exhaustif sur l’habitat, mais offre un panorama des connaissances et des enjeux actuels. Elle met en évidence les différentes dimensions du logement dans le contexte de la croissance démographique et de la fragmentation sociale, révèle les controverses et débats à son sujet et pointe les principaux enjeux pour le futur.Deze synthesenota verduidelijkt de verschillende aspecten van de huidige huisvestingsproblematiek in Brussel vanuit verschillende invalshoeken (demografisch, juridisch, politiek en sociologisch). De nota verstrekt geen exhaustieve stand van zaken van de kennis over de woonomgeving, maar biedt een overzicht van de huidige kennis en actuele uitdagingen. De nota licht de verschillende dimensies van de huisvestingsproblematiek toe in de context van de demografische groei en de sociale fragmentering, brengt de controverses en debatten over dat vraagstuk aan het licht en stipt de grootste uitdagingen voor de toekomst aan

Differential effect of Fas activation on spinal muscular atrophy motoneuron death and induction of axonal growth

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most common motoneuron diseases affecting adults and infants, respectively. ALS and SMA are both characterized by the selective degeneration of motoneurons. Although different in their genetic etiology, growing evidence indicates that they share molecular and cellular pathogenic signatures that constitute potential common therapeutic targets. We previously described a motoneuron-specific death pathway elicited by the Fas death receptor, whereby vulnerable ALS motoneurons show an exacerbated sensitivity to Fas activation. However, the mechanisms that drive the loss of SMA motoneurons remain poorly understood. Here, we describe an in vitro model of SMA-associated degeneration using primary motoneurons derived from Smn2B/- SMA mice and show that Fas activation selectively triggers the death of the proximal motoneurons. Fas-induced death of SMA motoneurons has the molecular signature of the motoneuron-selective Fas death pathway that requires activation of p38 kinase, caspase-8, -9 and -3 as well as upregulation of collapsin response mediator protein 4 (CRMP4). In addition, Rho-associated Kinase (ROCK) is required for Fas recruitment. Remarkably, we found that exogenous activation of Fas also promotes axonal elongation in both wildtype and SMA motoneurons. Axon outgrowth of motoneurons promoted by Fas requires the activity of ERK, ROCK and caspases. This work defines a dual role of Fas signaling in motoneurons that can elicit distinct responses from cell death to axonal growth

PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cell