Zebrafish models of neurodegenerative disorders as tools to decipher pathophysiological mechanisms and identify therapeutic drugs

Zebrafish models of neurodegenerative disorders as tools to decipher pathophysiological mechanisms and identify therapeutic drugs

Main research projects

Neurons expressing human pathological Tau (red) and microglia (green) in the zebrafish embryonic brain

Neurons expressing human pathological Tau (red) and microglia (green) in the zebrafish embryonic brain

Inherited neurodegenerative diseases are a large family of disorders whose symptom onset ranges from early childhood onward up to an advanced age. Over the last 20 years, the identification of causal mutations for a wide range of neurodegenerative disorders have allowed the generation of transgenic animal models, which have tremendously increased our knowledge of the processes underlying these diseases. However, in spite of the progresses gained, the mechanisms underlying the pathophysiology of the vast majority of these disorders remain largely unknown and no efficient pharmacological treatments have been so far identified. In this context, the zebrafish provides us with a vertebrate model that is beyond compare as it allows investigating the pathological processes in vivo, in the physiological context of an intact brain. Other advantages of this small and easy breeding fish include its genetic tractability (transgenesis and genome-editing technologies) and its amenability to medium-to-high throughput drug screening.

A recent breakthrough in our knowledge of the pathophysiology of neurodegenerative diseases lies in the identification of microglial cell-mediated neuroinflammation as a key element in the pathological process. Although these resident macrophages of the brain vertebrate serve both immune-related and glial functions, recent data suggest that the “friendly” microglial cells become a “foe” in several neuropathological contexts and contribute directly to the neurodegenerative process. To circumvent the limitations of rodent models and seek to better understand the contributions of microglial cells to the physiopathology of neurodegenerative tauopathies, we took advantage of a zebrafish transgenic line that reproduces key pathological features of neurodegenerative disorders in transgenic larvae. This line previously allowed us to identify sulphated glycoaminoglycans as key modulators of neurodegenerative processes.

The first main objective of our research projects is to find out more about the complex relationships that link diseased neurons and microglial cells. Specifically, we will seek to characterize: (i) the molecular pathways underlying microglia activation in different pathological contexts, and also (ii) the consequences of microglia activation on neuron pathology.

Our second general objective is to examine the promotion of beneficial microglial responses as a novel therapeutic approach to mitigate or alleviate neuron degeneration. Particularly, we will seek to devise therapeutic screens based on the motility defects of transgenic zebrafish larvae and an automated device that allows recording the motions of hundreds of larvae simultaneously.

Our third objective is to take advantage of zebrafish mutants and gene-KO technologies to seek to better understand the physiopathology of Friedreich’s ataxia, the most common inherited recessive ataxia in the Caucasian population, which is caused by severely decreased expression of the mitochondrial frataxin protein.

Members of the research group

  • Nadia Soussi-Yanicostas (chercheur CNRS)
  • Constantin Yanicostas (chercheur CNRS)
  • Rahma Hassan-Abdi (doctorante)
  • Amina Lebcir (IR, Inserm)
  • Christiane Romain (TCN Inserm)
  • Olivier Bar (TCN Inserm)

Main publications 2010-2015

  • Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies? Alavi Naini SM, Soussi-Yanicostas N. Oxid Med Cell Longev. 2015; 2015:151979.

  • HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer’s disease-related tau pathology. Alavi Naini SM, Sepulveda-Diaz JE, Huynh MB, Ouidja MO, Yanicostas C, Chantepie S, Villares J, Lamari F, Jospin E, van Kuppevelt TH, Mensah-Nyagan AG, Raisman-Vozari R, Papy-Garcia D, Soussi-Yanicostas N. Brain. 2015 138(5): 1339-54.

  • Evolutionary conservation of early mesoderm specifcation by mechanotransduction in Bilateria. Brunet T, Bouclet A, Ahmadi P, Mitrossilis D, Driquez B, Brunet AC, Henry L, Serman F, Béalle G, Ménager C, Dumas-Bouchiat F, Givord D, Yanicostas C, Le-Roy D, Dempsey NM, Plessis A, Farge E. Nat Commun. 2013; 4: 2821. doi: 10.1038/ncomms3821.

  • ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome. Ghoumid J, Drevillon L, Alavi-Naini SM, Bondurand N, Rio M, Briand-Suleau A, Nasser M, Goodwin L, Raymond P, Yanicostas C, Goossens M, Lyonnet S, Mowat D, Amiel J, Soussi-Yanicostas N, Giurgea I. Hum Mol Genet. 2013 22(13): 2652-61.

  • Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons. Yanicostas C, Barbieri E, Hibi M, Brice A, Stevanin G, Soussi-Yanicostas N. PLoS One. 2012; 7(11): e50705. doi: 10.1371/journal.pone.0050705. Epub 2012 Nov 30.

  • Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish. Martin E, Yanicostas C, Rastetter A, Naini SM, Maouedj A, Kabashi E, Rivaud-Péchoux S, Brice A, Stevanin G, Soussi-Yanicostas N. Neurobiol Dis. 2012 48(3): 299-308. doi: 10.1016/j.nbd.2012.07.003.

  • Localization and characterization of kal 1.a and kal 1.b in the brain of adult zebrafish (Danio rerio). Ayari B, Landoulsi A, Soussi-Yanicostas N. Brain Res Bull. 2012 88(4): 345-53.

  • Developmental aspects of respiratory chain from fetus to infancy. Yanicostas C, Soussi-Yanicostas N, El-Khoury R, Bénit P, Rustin P. Semin Fetal Neonatal Med. 2011 16(4): 175-80

  • Prokineticin 2 expression is associated with neural repair of injured adult zebrafish telencephalon. Ayari B, El Hachimi KH, Yanicostas C, Landoulsi A, Soussi-Yanicostas N. J Neurotrauma. 2010 27(5): 959-72.

  • Dynamic roles of FGF-2 and Anosmin-1 in the migration of neuronal precursors from the subventricular zone during pre- and postnatal development. García-González D, Clemente D, Coelho M, Esteban PF, Soussi-Yanicostas N, de Castro F. Exp Neurol. 2010 222(2): 285-95.