Neural stem cells in Huntington disease and aging

Objectives

In a mouse model of Huntington disease (HD), the candidate will: i) evaluate the maintenance of stem cells in the testis, skin and intestine; ii) determine whether proliferation and neural differentiation are affected and iii) whether metformin can restore these effects.

Abstract

Neurogenesis, the process by which new neurons are added from a resident pool of stem cells, is decreased in Huntington disease (HD). HD is a genetic neurological disorder with autosomal dominant transmission of the mutated huntingtin (HTT) gene. Onset of the disease occurs around 40 years old and is characterized by a triad of motor, cognitive and psychiatric symptoms. The HD mutation consists of an abnormal expansion of a CAG repeat, exceeding 35, in the HTT gene coding for a polymorphic polyglutamine (polyQ) stretch. Mutant HTT (mHTT) is toxic for neurons. In HD, neurogenesis is decreased in the dentate gyrus of the hippocampus in humans but also in the subventricular zone of rodents, impairing odor discrimination and memory. Our previous data showed that mHTT accelerates aging, depleting the stem cell pool which impairs neurogenesis. As mHTT is widely expressed throughout the organism, we speculate that other stem cell pools are affected. Also, we hypothesize that treating HD mice with a senomorphic may restore neurogenesis.

Methods

Western blot, cell culture, immunocytochemistry, histochemistry, flow cytometry, microscopy.

Reference

Barnat M, Capizzi M, Aparicio E, Boluda S, Wennagel D, Kacher R, Kassem R, Lenoir S, Agasse F, Braz BY, Liu JP, Ighil J, Tessier A, Zeitlin SO, Duyckaerts C, Dommergues M, Durr A, Humbert S (2020). Huntington's disease alters human neurodevelopment. Science, 369(6505):787-793.

Agasse F, Mendez-David I, Christaller W, Carpentier R, Braz BY, David DJ, Saudou F, Humbert S. (2020) Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin. Cell Rep., 32(1):107865.

Requested domains of expertise

Neuroscience, Cellular biology.

Contact

Fabienne Agasse, MCU
Email : %20fabienne.agasseuniv-grenoble-alpes.fr (fabienne[dot]agasse[at]univ-grenoble-alpes[dot]fr)
Phone : 04 56 52 05 11