Neuronal Stress and Ageing (NSA)

Neural circuits are responsible for the brain’s ability to process and store information. Our team is a pioneer one in the development of neural system-on-chip to control neuronal connectivity in vitro and in the construction of living neuronal network to study neurodegenerative diseases.

These neural systems-on-chips are microscale devices that combine cell culture methods with microfabrication and microfluidics technologies to mimic the cellular microenvironment accurately. The aim of these devices is to reproduce neural tissue- and brain-level functions accurately by developing only the most basic functional units and not the entire organ. Our goals are to establish on-chip living neural circuits of increasing complexity and precision, to establish neurodegenerative models-on-chip, explore mechanisms of neurodegeneration, and to decipher neurodegenerative pathways and define druggable targets (e.g. Casp2). Further advances in on-chip neural circuits may lead to better understanding of the brain, and may have important implication for drug discovery, such as screening drugs in a cost-effective manner and reduce animal studies.

https://www.caltech.edu/campus-life-events/master-calendar/distinguished-medical-engineering-seminar-26

3 main axes: 

  1. The development of microfluidic technology and methods of (co) cultures with defined architectures (e.g. Neural circuit-on-Chip) ;
  2. The role of NAD+, its precursor nicotinamide riboside (NR), and the importance of its metabolism during neuronal stresses (e.g. excitotoxicity, b-Amyloid peptide, Parkinson-like stress) ;
  3. Targeting synaptic Caspase-2 in neurodegenerative models.


Recent Patents:

E. Jacotot. WO2016112961A1. Caspase-2 conditional Knockouts and methods. European Patent Application PCT/EP2015/050512 filed January 2015

E Jacotot. WO2017162674 A1. Novel derivatives and their use as selective inhibitors of caspase-2. European Patent Application PCT/EP2017/056696  21 march 2017E Jacotot, E. Bosc. Novel compounds and their use as selective inhibitors of Caspase-2. European Patent Application PCT/ EP2017/ EP17306270.4 filed 26 sept 2017. 

Recent Publications:

Selective caspase-2 inhibition and synapse protection with a new irreversible pentapeptide derivative. Bosc E, Anastasie J, Soulami F , Pretat S, Lacin G, Duplus E , Tixador P , Cochet H., Brugg B , El Amri C, Jacotot E. Cell Death Discovery 2019,5:54. https://www.nature.com/articles/s41420-018-0128-4.pdf

Propagation of ?-Synuclein Strains within Human Reconstructed Neuronal Network. Gribaudo S*, Tixador P*, Bousset L, Fenyi A, Lino P, Melki R, Peyrin JM, Perrier AL. Stem Cell Reports. 2019 Feb 12;12(2):230-244.

Reconstruction of directed neuronal networks in a microfluidic device with asymmetric microchannels. Courte J, Renault R, Jan A, Viovy JL, Peyrin JM, Villard C. Methods Cell Biol. 2018;148:71-95.

Dysregulated Neurotransmission induces Trans-synaptic degeneration in reconstructed Neuronal Networks. Deleglise B, Lassus B, Soubeyre V, Doulazmi M, Brugg B, Vanhoutte P, Peyrin JM. Sci Rep. 2018 Aug 2;8(1):11596.

Glutamatergic and dopaminergic modulation of cortico-striatal circuits probed by dynamic calcium imaging of networks reconstructed in microfluidic chips. Lassus B, Naudé J, Faure P, Guedin D, Von Boxberg Y, Mannoury la Cour C, Millan MJ, Peyrin JM. Sci Rep. 2018 Nov 29;8(1):17461. 

Neurotoxicity of the Cyanotoxin BMAA Through Axonal Degeneration and Intercellular Spreading. Tan VX, Lassus B, Lim CK, Tixador P, Courte J, Bessede A, Guillemin GJ, Peyrin JM. Neurotox Res. 2018 Jan;33(1):62-75.

Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults. Lassus BMagnifico S, Pignon S, Belenguer P, Miquel MC, Peyrin JM. Sci Rep. 2016 Sep 8;6:32777. 

Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. Vaur P, Brugg B, Mericskay M, Li Z, Schmidt MS, Vivien D, Orset C, Jacotot E, Brenner C, Duplus E. FASEB J. 2017 Dec;31(12):5440-5452. 

beta-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network.  Deleglise B, Magnifico S, Duplus E, Vaur P, Soubeyre V, Belle M, Vignes M, Viovy JL, Jacotot EPeyrin JM, Brugg B. Acta Neuropathol Commun. 2014 Sep 25;2:145.