A Mechanism Underpinning the Bioenergetic Metabolism-Regulating Function of Gold Nanocatalysts
Zixin Wang, Alexandre Henriques, Laura Rouvière, Noëlle Callizot, Lin Tan, Michael T. Hotchkin, Rodrigue Rossignol, Mark G. Mortenson, Adam R. Dorfman, Karen S. Ho, Hui Wang
Published: September 28, 2023.
Bioenergetic deficits are known to be significant contributors to neurodegenerative diseases. Nevertheless, identifying safe and effective means to address intracellular bioenergetic deficits remains a significant challenge. This work provides mechanistic insights into the energy metabolism-regulating function of colloidal Au nanocrystals, referred to as CNM-Au8, that are synthesized electrochemically in the absence of surface-capping organic ligands. When neurons are subjected to excitotoxic stressors or toxic peptides, treatment of neurons with CNM-Au8 results in dose-dependent neuronal survival and neurite network preservation across multiple neuronal subtypes. CNM-Au8 efficiently catalyzes the conversion of an energetic cofactor, nicotinamide adenine dinucleotide hydride (NADH), into its oxidized counterpart (NAD+), which promotes bioenergy production by regulating the intracellular level of adenosine triphosphate. Detailed kinetic measurements reveal that CNM-Au8-catalyzed NADH oxidation obeys Michaelis–Menten kinetics and exhibits pH-dependent kinetic profiles. Photoexcited charge carriers and photothermal effect, which result from optical excitations and decay of the plasmonic electron oscillations or the interband electronic transitions in CNM-Au8, are further harnessed as unique leverages to modulate reaction kinetics. As exemplified by this work, Au nanocrystals with deliberately tailored structures and surfactant-free clean surfaces hold great promise for developing next-generation therapeutic agents for neurodegenerative diseases.
Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence
Alexandre Henriques (1)(2), Laura Rouvière (1), Elodie Giorla (2), Clémence Farrugia (2), Bilal El Waly (2), Philippe Poindron (1)(2) and Noelle Callizot (1)(2)
(1) Neuro-Sys, In Vitro Pharmacology Department, 13120 Gardanne, France
(2) Neuro-Sys Vivo, 13120 Gardanne, France
Published: August 30, 2022.
Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson’s disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures of dopaminergic neurons or on aged mice after infusion in the SNpc and combined with mild inhibition of GBA. In primary dopaminergic neurons, application of α-syn PFF induced a progressive cytotoxicity associated with mitochondrial dysfunction, oxidative stress, and accumulation of lysosomes suggesting that exogenous α-syn reached the lysosome (from the endosome). Counteracting the α-syn endocytosis with a clathrin inhibitor, dopaminergic neuron degeneration was prevented. In vivo, α-syn PFF induced progressive neurodegeneration of dopaminergic neurons associated with motor deficits. Histology revealed progressive aggregation of α-syn and microglial activation and accounted for the seeding role of α-syn, injection of which acted as a spark suggesting a triggering of cell-to-cell toxicity. We showed for the first time that a localized SNpc α-syn administration combined with a slight lysosomal deficiency and aging triggered a progressive lesion. The cellular and animal models described could help in the understanding of the human disease and might contribute to the development of new therapies.
NX210c Peptide Promotes Glutamatergic Receptor-Mediated Synaptic Transmission and Signaling in the Mouse Central Nervous System
Sighild Lemarchant (1), Mélissa Sourioux (1), Juliette Le Douce (1), Alexandre Henriques (2), Noelle Callizot (2), Sandrine Hugues (3), Mélissa Farinelli (3) and Yann Godfrin (1)(4)
(1) Axoltis Pharma, 60 Avenue Rockefeller, 69008 Lyon, France
(2) Neuro-Sys, 410 Chemin Départemental 60, 13120 Gardanne, France
(3) E-Phy-Science, Bioparc, 2400 Routes de Colles, Sophia Antipolis, 06410 Biot, France
(4) Godfrin Life-Sciences, 8 Impasse de la Source, 69300 Caluire-et-Cuire, France
Published: August 9, 2022.
NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory postsynaptic currents in the brain. Accordingly, using extracellular field excitatory postsynaptic potential recordings, an enhancement of synaptic transmission was shown in the presence of NX210c in two different neuronal circuits. Furthermore, the modulation of synaptic transmission and GluN2A-NMDAR-driven signaling by NX210c restored memory in mice chronically treated with the NMDAR antagonist phencyclidine. Overall, by promoting glutamatergic receptor-related neurotransmission and signaling, NX210c represents an innovative therapeutic opportunity for patients suffering from CNS disorders, injuries, and states with crippling synaptic dysfunctions.
Huperzia serrata Extract ‘NSP01’ With Neuroprotective Effects-Potential Synergies of Huperzine A and Polyphenols
N. Callizot (1), ML Campanari (1), L Rouvière (1), G Jacquemot (2), A. Henriques (1), E Garayev (2) and P. Poindron (1)
(1) Neuro-Sys SAS, Neuro-Pharmacology Department, Gardanne, France
(2) Neuralia SAS, Gardanne, France
Published: August 30, 2021.
Huperzia serrata (Thunb.) Trevis is widely used in traditional asiatic medicine to treat many central disorders including, schizophrenia, cognitive dysfunction, and dementia. The major alkaloid, Huperzine A (HA), of H. serrata is a well-known competitive reversible inhibitor of acetylcholinesterase (AChE) with neuroprotective effects. Inspired by the tradition, we developed a green one-step method using microwave assisted extraction to generate an extract of H. serrata, called NSP01. This green extract conserves original neuropharmacological activity and chemical profile of traditional extract. The neuroprotective activity of NSP01 is based on a precise combination of three major constituents: HA and two phenolic acids, caffeic acid (CA) and ferulic acid (FA). We show that CA and FA potentiate HA-mediated neuroprotective activity. Importantly, the combination of HA with CA and FA does not potentiate the AChE inhibitory property of HA which is responsible for its adverse side effects. Collectively, these experimental findings demonstrated that NSP01, is a very promising plant extract for the prevention of Alzheimer’s disease and memory deficits.
AZP2006, a new promising treatment for Alzheimer’s and related diseases
N Callizot, C Estrella, S Burlet, A Henriques, C Brantis, M Barrier, M L Campanari, P Verwaerde
Alzprotect, Parc Eurasanté, 85C rue Nelson Mandela, 59120, Loos, France.
Neuro-Sys, 410 Chemin Départemental 60, 13120, Gardanne, France.
Published: August 19, 2021.
Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1-42 and in two different pathological animal models of Alzheimer's disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.
Para-Substituted α-Phenyl- N- tert-butyl Nitrones: Spin-Trapping, Redox and Neuroprotective Properties
Published: December 08, 2020.
In this work, a series of para-substituted α-phenyl-N-tert-butyl nitrones (PBN) were studied. Their radical-trapping properties were evaluated by electron paramagnetic resonance, with 4-CF3-PBN being the fastest derivative to trap the hydroxymethyl radical (•CH2OH). The redox properties of the nitrones were further investigated by cyclic voltammetry, and 4-CF3-PBN was the easiest to reduce and the hardest to oxidize. This is due to the presence of the electron-withdrawing CF3 group. Very good correlations between the Hammett constants (σp) of the substituents and both spin-trapping rates and redox potentials were observed. These correlations were further supported by computationally determined ionization potentials and atom charge densities. Finally, the neuroprotective effect of these derivatives was studied using two different in vitro models of cell death on primary cortical neurons injured by glutamate exposure or on glial cells exposed to t BuOOH. Trends between the protection afforded by the nitrones and their lipophilicity were observed. 4-CF3-PBN was the most potent agent against t BuOOH-induced oxidative stress on glial cells, while 4-Me2N-PBN showed potency in both models.
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.
Posters / Alzheimer's disease
Posters / Parkinson's disease
Posters / ALS
Posters / Chemotherapy-Induced Peripheral Neuropathy
Posters / BBB
R&D Programs + Collaborations
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
(in 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.
ANNOUNCEMENT - December 18, 2019:
Neuro-Sys and Sciomics announce a collaboration to co-develop an unrivaled integrated preclinical solution in neurodegenerative disorders.
A new step forward in neurodegenerative disease research
Neuro-Sys and Sciomics announce a collaboration to co-develop an unrivaled integrated preclinical solution in neurodegenerative disorders.
December 18, 2019 06:57 PM Eastern Standard Time
GARDANNE, France and HEIDELBERG, Germany – The French biotech company Neuro-Sys SAS and the German biotech company Sciomics GmbH today announced that they are joining their R&D forces to study the proteome and the phosphoproteome in preclinical models of Alzheimer’s, Parkinson’s and ALS diseases to investigate the proteomic and phosphoproteomic profile of these disease models. The aim is to better understand the mechanisms involved in the neurodegenerative process and to provide new solutions for characterizing the efficacy and mode-of-action of neuroprotective compounds.
The changes in the proteome (protein level) and phosphoproteome (phosphorylation status of proteins) will be determined by the scioPhospho platform using advanced in vitro models of Alzheimer’s disease (focused on the chronic and the acute toxicity of the beta amyloid oligomers, AβO), Parkinson’s disease (with a specific attention to the mitochondrial disorders), and amyotrophic lateral sclerosis (focused on the hypersensitivity to glutamate stressor). In addition, the inflammatory component will be analyzed (cytokine release profile).
Identified proteomic changes will be correlated with neuronal survival and proteinopathies detected by immunostaining (e.g. hyperphosphorylation of Tau ; alpha-synuclein aggregation ; translocation of TDP-43).
“For many years, we have been thoroughly investigating the mechanisms occurring in these neurodegenerative diseases. We have developed advanced in vitro models of these diseases in which the mechanisms and the pathways involved in the process of death are carefully studied through our intensive internal research and partnerships”, said Noelle Callizot, PharmD, Ph.D., Chief Scientific Officer at Neuro-Sys. “We believe that the collaboration with Sciomics is a great opportunity to better understand pathophysiological pathways and to help our partners in the development of new therapeutic approaches.”
“Over the last decade we have developed an efficient and robust platform for profiling protein levels and phosphorylation status.”, said Dr. Christoph Schröder, Chief Executive Officer at Sciomics. “By a combination of the profound expertise and advanced pre-clinical models of Neuro-Sys with our in-depth protein readout options, we are looking forward to foster novel insights and developments in the important field of neurodegenerative disorders.”
Preliminary results are expected to be released early 2020.
Neuro-Sys is an expert in preclinical in vitro models of neurodegenerative and neurological diseases. It has developed specific models to accurately determine the pharmacological profiling of lead compounds and explore their underlying mechanism of action. With a great team of experts and an innovative proprietary automated medium throughput platform combined with advanced models, it provides reliable results and a unique approach in the neurodegenerative diseases research.
The company’s many loyal pharma and biotech customers around the world are the best testimony to the efficiency and reliability of its solution.
Sciomics has extensive expertise in the area of biomarker discovery, in vitro as well as in vivo model system characterisation and disease mechanism profiling using its high-content protein and post-translational modification profiling platform in an analysis service setting and for internal research. More than 1,000 proteins are currently analysed by the proprietary fully immuno-based scioDiscover antibody array platform in a single assay with minimal sample requirements. Information on the protein abundance can be combined with the phosphorylation, ubiquitination or methylation status of these proteins. The high-content and high-throughput platform guarantees robust and reproducible results which – due to its immuno-based nature - can easily be translated into validation as well as clinical assays.
The platform’s main applications are the discovery of protein biomarkers, screening and verification of new drug targets, pathway activity profiling as well as drug mode-of-action analysis.
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.