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The last two years in scientific news
> CO-DIRECTION :
Alexis BEMELMANS (CEA)
Research focus and objectives of the team
Our working hypothesis is that the selective neuronal dysfunctions and death occurring in many neurodegenerative diseases originate not only from neuron-intrinsic impairments but also from the convergence of dysfunctions and damages developed within multiple cell types in specific brain areas. This includes synaptic interactions between the most vulnerable neurons within neuronal networks (e.g. striatal and cortical neurons in Huntington's disease), as well as functional interactions between these neurons and neighboring glial cells such as astrocytes or microglia. In order to interrogate the respective role of specific cell populations, we are developing innovative in cellulo (rodent primary neural cultures and human induced pluripotent stem cells (iPS)) and in vivo (rodents and non-human primates with Team 6) models of Huntington's, Parkinson's and Alzheimer's disease with viral vectors. In parallel we make use of the biological resources, tools and models created to design, develop and assess new biotherapies including in particular gene and substitutive cell therapy approaches. Overall, we aim at:
1.Investigate the molecular basis of regional vulnerability in neurodegenerative diseases
2. Elucidate the role of neuron-glia interactions during the course of neurodegeneration
3.Design and assess innovative biotherapies for neurodegenerative diseases
You will find below the summary of two research projects that are ongoing in the team.
Tauopathies are characterized by the progressive accumulation of abnormal forms of Tau protein in the brain. Most often, Tau aggregates are found in neurons, but in some tauopathies, Tau aggregates are also detected in astrocytes. Yet both their origin and the consequences of their accumulation are unknown.
In collaboration with Université de Lille, we developed rodent models of tauopathies overexpressing tau variants with a distinct propensity to aggregate. We showed that astrocytic Tau pathology can be secondary to neuronal pathology. Using new gene transfer-based tools, we also demonstrated a transfer of Tau between neurons and astrocytes. We found severe toxicity of soluble hyperphosphorylated forms of Tau for specific populations of astrocytes. Our data suggest that astrocytes are not mere bystanders of neuronal pathology and that Tau pathology in astrocytes may significantly contribute to clinical symptoms.
Figure 1 : Our working hypothesis
is based on the bi-directional exchange of pathological Tau protein between
neurons and astrocytes (left). Confocal image showing the presence of
hyperphosphorylated Tau (AT100, red) in neurons and in one astrocyte (GFAP
green, white arrow) in 18-month old Thy-Tau22- mouse (right).
Figure 1 : Notre hypothèse de travail est basée sur l'échange bidirectionnel de protéine Tau pathologique entre les neurones et les astrocytes (à gauche). Image confocale montrant la présence de Tau hyperphosphorylée (AT100 en rouge) dans les neurones et dans un astrocyte (GFAP en vert, flèche blanche) chez la souris Thy-Tau22 de 18 mois (à droite).
Along with astrocytes, microglial cells are involved in the neuroinflammatory response to Tauopathy. The variants of TREM2, a cell surface receptor expressed by microglia, confer a risk of developing AD comparable to the ε4 allele of the APOE gene. This suggests that in addition to responding to the pathological process, these glial cells may actually play a key role in the emergence of the disease. We investigated the impact of TREM2 deficiency on the severity of Tauopathy in the THY-Tau22 transgenic line, a well-characterized model of tauopathy. We found an increase in the severity of tauopathy in TREM2-deficient mice. This exacerbation of the pathology was associated with a reduction in microglial activation indicated by typical morphological features and altered expression of specific markers. Our study confirms that a defect in microglial TREM2 signaling leads to an increase in neuronal tauopathy.
Figure 2 : AT100 staining showing
the increase accumulation of tauopathy in the CA1 layer of the hippocampus in
12-month-old Tau22 mice deficient for Trem2 (Vautheny et al., Neurobiology of
Neuratris – Innovation for translational neuroscience: Contribution of glial cells to synaptic phagocytosis in Tauopathies (2021-22)
Neuratris – Innovation for translational neuroscience: Satellite glial cell-proprioceptor interactions: implications for spinal muscular atrophy, amyotrophic lateral sclerosis and Friedreich's ataxia (2020-22)
Astrocyte-neuron metabolic cooperation shapes brain activity. Bonvento G, Bolaños JP. Cell Metab. 2021 Aug 3;33(8):1546-1564. doi:10.1016/j.cmet.2021.07.006
Neuronal Tau species transfer to astrocytes and induce their loss according to Tau aggregation state. Maté de Gérando Anastasie, d'Orange Marie, Augustin Emma, Joséphine Charlène, Aurégan Gwénaelle, Gaudin-Guérif Mylène, Guillermier Martine, Hérard Anne- Sophie, Stimmer Lev, Petit Fanny, Gipchtein Pauline, Jan Caroline, Escartin Carole, Selingue Erwan, Carvalho Kévin, Blum David, Brouillet Emmanuel, Hantraye Philippe, Gaillard Marie-Claude, Bonvento Gilles, Bemelmans Alexis-Pierre, Cambon Karine. BRAIN, April 2021, https://doi.org/10.1093/brain/awab011
The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo. Cresto N, Gardier C, Gaillard MC, Gubinelli F, Roost P, Molina D, Josephine C, Dufour N, Auregan G, Guillermier M, Bernier S, Jan C, Gipchtein P, Hantraye P, Chartier-Harlin MC, Bonvento G, Van Camp N, Taymans JM, Cambon K, Liot G, Bemelmans AP, Brouillet E. Int J Mol Sci. 2021 Jun 22(13):6760. doi: 10.3390/ijms22136760.
THY-Tau22 mouse model accumulates more tauopathy at late stage of the disease in response to microglia deactivation through TREM2 deficiency. Vautheny A, Duwat C, Aurégan G, Joséphine C, Hérard AS, Jan C, Mitja J, Gipchtein P, Gaillard MC, Buée L, Blum D, Hantraye P, Bonvento G, Brouillet E, Cambon K, Bemelmans AP. Neurobiology of Disease 2021 Jul;155:105398. doi: 10.1016/j.nbd.2021.105398. Epub 2021 May 18.
Impairment of glycolysis-derived L-serine production in astrocytes contributes to cognitive deficits in Alzheimer's disease Le Douce J, Maugard M, Veran J, Matos M, Jégo P, Vigneron P-A, Faivre E, Toussay X, Vandenberghe M, Balbastre Y, Piquet J, Guiot E, Nguyet Thuy Tran, Taverna M, Marinesco S, Koyanagi A, Furuya S, Gaudin-Guérif M, Goutal S, Ghettas A, Pruvost A, Bemelmans AP, Gaillard M-C, Cambon K, Stimmer L, Sazdovitch V, Duyckaerts C, Knott G, Hérard A-S, Delzescaux T, Hantraye P, Brouillet E, Cauli B,. Oliet S, Panatier A, Bonvento G. Cell Metabolism, 2020 Mar 3;31(3):503-517.e8. doi: 10.1016/j.cmet.2020.02.004.
MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates. Romina Aron Badin, Aurore Bugi , Susannah Williams , Marta Vadori , Marie Michael , Caroline Jan, Alberto Nassi, Sophie Lecourtois, Antoine Blancher , Emanuele Cozzi , Philippe Hantraye , Anselme L Perrier Nat Commun 2019 Sep 25;10(1):4357. doi: 10.1038/s41467-019-12324-0.
Propagation of α-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. doi: 10.1016/j.stemcr.2018.12.007. Epub 2019 Jan 10.
The C-terminal domain of LRRK2 with the G2019S mutation is sufficient to produce neurodegeneration of dopaminergic neurons in vivo. Cresto N, Gaillard MC, Gardier C, Gubinelli F, Diguet E, Bellet D, Legroux L, Mitja J, Auregan G, Guillermier M, Josephine C, Jan C, Dufour N, Joliot A, Hantraye P, Bonvento G, Déglon N, Bemelmans AP, Cambon K, Liot G, Brouillet E. Neurobiology of Disease 2019 Oct 9:104614. doi: 10.1016/j.nbd.2019.104614.
Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat. d'Orange M, Aurégan G, Cheramy D, Gaudin-Guérif M, Lieger S, Guillermier M, Stimmer L, Joséphine C, Hérard AS, Gaillard MC, Petit F, Kiessling MC, Schmitz C, Colin M, Buée L, Panayi F, Diguet E, Brouillet E, Hantraye P, Bemelmans AP, Cambon K. BRAIN 2018 Feb 1;141(2):535-549. doi: 10.1093/brain/awx342.
The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin. Galvan L, Francelle L, Gaillard MC, de Longprez L, Carrillo-de Sauvage MA, Liot G, Cambon K, Stimmer L, Luccantoni S, Flament J, Valette J, de Chaldée M, Auregan G, Guillermier M, Joséphine C, Petit F, Jan C, Jarrige M, Dufour N, Elalouf JM , Bonvento G, Humbert S, Saudou F, Hantraye P, Merienne K, Bemelmans AP, Perrier A, Déglon N, Brouillet E. BRAIN May 1;141(5):1434-1454. doi: 10.1093/brain/awy057.
Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing. Cambon K, Zimmer V, Martineau S, Gaillard MC, Jarrige M, Bugi A, Miniarikova J, Rey M, Hassig R, Dufour N, Auregan G, Hantraye P, Perrier AL, Déglon N. Mol Ther Methods Clin Dev. 2017 May 11;5:259-276. doi: 10.1016/j.omtm.2017.05.001.
mRNA trans-splicing in gene therapy for genetic diseases. Berger A, Maire S, Gaillard MC, Sahel JA, Hantraye P, Bemelmans AP. Wiley Interdisciplinary Reviews RNA 2016 Jul;7(4):487-98. doi: 10.1002/wrna.1347. Epub 2016 Mar 28.
Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa. Berger A, Lorain S, Joséphine C, Desrosiers M, Peccate C, Voit T, Garcia L, Sahel JA, Bemelmans AP. Molecular Therapy 2015 May;23(5):918-930. doi: 10.1038/mt.2015.11. Epub 2015 Jan 26.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.