ALS: A Disease of Motor Neurons and Their Nonneuronal Neighbors

Amyotrophic lateral sclerosis is a late-onset progressive neurodegenerative disease affecting motor neurons. The etiology of most ALS cases remains unknown, but 2% of instances are due to mutations in Cu/Zn superoxide dismutase (SOD1). Since sporadic and familial ALS affects the same neurons with similar pathology, it is hoped that therapies effective in mutant SOD1 models will translate to sporadic ALS. Mutant SOD1 induces non-cell-autonomous motor neuron killing by an unknown gain of toxicity. Selective vulnerability of motor neurons likely arises from a combination of several mechanisms, including protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, excitotoxicity, insufficient growth factor signaling, and inflammation. Damage within motor neurons is enhanced by damage incurred by nonneuronal neighboring cells, via an inflammatory response that accelerates disease progression. These findings validate therapeutic approaches aimed at nonneuronal cells

The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

International audienceMutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS

New insights on the disease contribution of neuroinflammation in ALS

International audiencePurpose of review: Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease with a strong neuroinflammatory component. This review summarizes how the connection between neurodegeneration and the immune system is strengthened by new discoveries from ALS genetics and the analysis of subpopulations of immune cells in ALS.Recent findings: Recent genes identified in ALS encode for proteins with direct immune roles, which when mutated lead to deregulation of immune functions, potentially influencing the disease. Although neuroinflammation in the central nervous system (CNS) of ALS patients has been well documented, new evidence suggests also direct malfunctions of immune cells in the CNS and at the periphery. Although CD4+ T-regulatory lymphocytes are protective in ALS, their number and function are altered over the disease course. CD8+ T cells are detrimental for motor neurons in the CNS but show some protective roles at the periphery. Similarly, the presence of mast cells in muscles of ALS models and patients and impairments of monocyte functions reveal potential new players in ALS disease progression.Summary: Although motor neuron degeneration is considered the prime event in ALS, dysfunctions in immune processes can impact the disease, highlighting that targeting specific immune components is a strategy for developing biomarkers and ultimately new drugs

Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons

Global, age-dependent changes in gene expression from rodent models of inherited ALS caused by dominant mutations in superoxide-dismutase 1 (SOD1) were identified by using gene arrays and RNAs isolated from purified embryonic and adult motor neurons. Comparison of embryonic motor neurons expressing a dismutase active ALS-linked mutant SOD1 with those expressing comparable levels of wild-type SOD1 revealed the absence of mutant-induced mRNA changes. An age-dependent mRNA change that developed presymptomatically in adult motor neurons collected by laser microdissection from mice expressing dismutase active ALS-linked mutants was dysregulation of the d/l-serine biosynthetic pathway, previously linked to both excitotoxic and neurotrophic effects. An unexpected dysregulation common to motor neurons expressing either dismutase active or inactive mutants was induction of neuronally derived components of the classic complement system and the regenerative/injury response. Alteration of these mutant SOD1-induced pathways identified a set of targets for therapies for inherited ALS

New advances in Amyotrophic Lateral Sclerosis genetics: towards gene therapy opportunities for familial and young cases

International audienceDue to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease

Effects of a Single Head Exposure to GSM-1800 MHz Signals on the Transcriptome Profile in the Rat Cerebral Cortex: Enhanced Gene Responses Under Proinflammatory Conditions

International audienceMobile communications are propagated by electromagnetic fields (EMFs), and since the 1990s, they operate with pulse-modulated signals such as the GSM-1800 MHz. The biological effects of GSM-EMF in humans affected by neuropathological processes remain seldom investigated. In this study, a 2-h head-only exposure to GSM-1800 MHz was applied to (i) rats undergoing an acute neuroinflammation triggered by a lipopolysaccharide (LPS) treatment, (ii) age-matched healthy rats, or (iii) transgenic hSOD1G93A rats that modeled a presymptomatic phase of human amyotrophic lateral sclerosis (ALS). Gene responses were assessed 24 h after the GSM head-only exposure in a motor area of the cerebral cortex (mCx) where the mean specific absorption rate (SAR) was estimated to be 3.22 W/kg. In LPS-treated rats, a genome-wide mRNA profiling was performed by RNA-seq analysis and revealed significant (adjusted p value < 0.05) but moderate (fold changes < 2) upregulations or downregulations affecting 2.7% of the expressed genes, including genes expressed predominantly in neuronal or in glial cell types and groups of genes involved in protein ubiquitination or dephosphorylation. Reverse transcription-quantitative PCR analyses confirmed gene modulations uncovered by RNA-seq data and showed that in a set of 15 PCR-assessed genes, significant gene responses to GSM-1800 MHz depended upon the acute neuroinflammatory state triggered in LPS-treated rats, because they were not observed in healthy or in hSOD1G93A rats. Together, our data specify the extent of cortical gene modulations triggered by GSM-EMF in the course of an acute neuroinflammation and indicate that GSM-induced gene responses can differ according to pathologies affecting the CNS