AMYOTROPHIC LATERAL SCLEROSIS
CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY
BLOOD BRAIN BARRIER
Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis.
Alexandra Bouscary, Cyril Quessada, Althéa Mosbach, Noëlle Callizot, Michael Spedding, Jean-Philippe Loeffler, Alexandre Henriques.
Published: August 7, 2019.
Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS. In particular, levels of ceramides, glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients. Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase. Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice. A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice. In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit. Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.
Necrosis, apoptosis, necroptosis, three modes of action of dopaminergic neuron neurotoxins.
Noelle Callizot, Maud Combes, Alexandre Henriques, Philippe Poindron.
Published: April 25, 2019.
Most of the Parkinson’s disease (PD) cases are sporadic, although several genes are directly related to PD. Several pathways are central in PD pathogenesis : protein aggregation linked to proteasomal impairments, mitochondrial dysfunctions and impairment in dopamine (DA) release. Here we studied the close crossing of mitochondrial dysfunction and aggregation of α-synuclein (α-syn) and in the extension in the dopaminergic neuronal death. Here, using rat primary cultures of mesencephalic neurons, we induced the mitochondrial impairments using “DA-toxins” (MPP+, 6OHDA, rotenone). We showed that the DA-Toxins induced dopaminergic cell death through different pathways : caspase-dependent cell death for 6OHDA ; MPP+ stimulated caspase-independent cell death, and rotenone activated both pathways. In addition, a decrease in energy production and/or a development of oxidative stress were observed and were linked to α-syn aggregation with generation of Lewy body-like inclusions (found inside and outside the dopaminergic neurons). We demonstrated that any of induced mitochondrial disturbances and processes of death led to α-syn protein aggregation and finally to cell death. Our study depicts the cell death mechanisms taking place in in vitro models of Parkinson’s disease and how mitochondrial dysfunctions is at the cross road of the pathologies of this disease.
Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing.
Boland B, Yu WH, Corti O, Mollereau B, Henriques A, Bezard E, Pastores GM, Rubinsztein DC, Nixon RA, Duchen MR, Mallucci GR, Kroemer G, Levine B, Eskelinen EL, Mochel F, Spedding M, Louis C, Martin OR, Millan MJ.
Nat Rev Drug Discov. 2018 Sep ;17(9):660-688. doi : 10.1038/nrd.2018.109. Epub 2018 Aug 17.
Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called ’proteinopathies’ owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic-lysosomal network. Several other clearance pathways are also compromised in NDAs : chaperone-mediated autophagy, the ubiquitin-proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood-brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.
Glutamate protects neuromuscular junctions from deleterious effects of β-amyloid peptide and conversely: An in vitro study in a nerve-muscle coculture.
Combes M, Poindron P, Callizot N.
J Neurosci Res. 2015 Apr ;93(4):633-43. doi : 10.1002/jnr.23524. Epub 2014 Dec 9.
Murine models of Alzheimer’s disease with elevated levels of amyloid-β (Aβ) peptide present motor axon defects and neuronal death. Aβ1-42 accumulation is observed in motor neurons and spinal cords of sporadic and familial cases of amyotrophic lateral sclerosis (ALS). Motor neurons are highly susceptible to glutamate, which has a role in ALS neuronal degeneration. The current study investigates the link between Aβ and glutamate in this neurodegenerative process. Primary rat nerve and human muscle cocultures were intoxicated with glutamate or Aβ. Neuromuscular junction (NMJ) mean size and neurite length were evaluated. The role of N-methyl-D-aspartate receptor (NMDAR) was investigated by using MK801. Glutamate and Aβ production were evaluated in culture supernatant. The current study shows that NMJs are highly sensitive to Aβ peptide, that the toxic pathway involves glutamate and NMDAR, and that glutamate and Aβ act in an interlinked manner. Some motor diseases (e.g., ALS), therefore, could be considered from a new point of view related to these balance disturbances.
Neuro-Sys is open to national, European and international scientific collaboration.
Our R&D department is dedicated to the development and characterisation of models of neurodegenerative diseases.
We investigate the pathological mechanisms involved in these diseases in order to provide relevant models for studying the efficacy and mode of action of therapeutic compounds.
Aside from our intern R&D programs, we are involved in collaborative projects with internationally renowned partners from academia and industry.
Chaperon project (supported by Eurostars program/H2020)
In collaboration with Gain Therapeutics SA (Switzerland) and the Institute for Research in Biomedicine (Switzerland), Neuro-Sys is supported by a European program in the development of novel and innovative models of lysosomal storage diseases (Gaucher’s disease, Krabbe’s disease, Hurler syndrome, GM1 gangliosidosis).This collaborative project is a great opportunity to gain insight into the mechanisms of these rare diseases and to support the development of new therapies.
Proteinopathy in neurodegenerative diseases (collaboration with Sciomics GmbH)
Proteinopathy is a common feature in neurodegenerative diseases. Protein clearance pathways represent promising therapeutic targets for these diseases to alleviate the protein burden.Neuro-Sys and Sciomics GmbH (Germany) have joined forces to study the proteome and the phosphoproteome in preclinical models of Alzheimer’s, Parkinson’s and ALS diseases to investigate the proteomic profiling of these disease models. The aim is to better understand the mechanisms involved in the neurodegenerative process and to provide new solutions for characterising the efficacy and mode of action of neuroprotective compounds.
Sphingolipids in Parkinson’s disease (collaboration with University of Milan) and amyotrophic lateral sclerosis (collaboration with University of Strasbourg)
Growing evidence connects complex sphingolipids to trophic signaling in neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis.
Together with Dr Elena Chiricozzi, from the University of Milan, we are dissecting the effects of complex sphingolipids on different pathologies of Parkinson’s disease (e.g. mitochondrial dysfunction, neuroinflammation).
In a second collaborative project with the Dr Jean-Philippe Loeffler, at the university of Strasbourg, we investigate the neuroprotective pathways linked to glycosphingolipids.