2022 Winners of the Jerome Lejeune Young Researcher Award
The recipients of the Jerome Lejeune Young Researcher Award 2022 are two young scientists that are completing or have completed their PhD thesis on intellectual disabilities of genetic origin
Louison Lallemant
Centre de Recherche en Myologie, Faculté de Médecine Sorbonne université
Site Pitié Salpêtrière, Paris, France.
Thesis title: Neuronal and glial pathology behind the neurological impairment of myotonic dystrophy type 1
Thesis advisor: Mario Gomes-Pereira
Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease affecting many tissues and organs. The debilitating neurological manifestations vary from executive dysfunction in adults, to attention deficits and low processing speed in pediatric patients, to severe intellectual disability in congenital cases. There is currently no treatment for this disease. DM1 is caused by the expansion of a CTG repeat in DMPK gene. Expanded DMPK transcripts are toxic because they accumulate in the cell nucleus, disrupting the activity of important RNA-binding proteins. As a consequence, DM1 cells show abnormal RNA metabolism and processing of many downstream transcripts. Despite progress in the understanding muscle pathophysiology, the disease mechanisms remain unclear in the CNS. Using a transgenic mouse model of DM1, I found significant defects in both neurons and astrocytes. At the neuronal level, DM1 mice showed abnormal neurotransmission and synaptic plasticity in the hippocampus. These functional phenotypes were associated with reduced neuritogenesis and abnormal intraneuronal vesicle dynamics. Through a multi-omics approach, I found that DM1 mouse neurons displayed splicing, expression and phosphorylation defects in transcripts and proteins involved in neuronal differentiation, morphology and vesicle transport. These molecular abnormalities likely contribute to the abnormal neurotransmission and neuronal phenotypes detected. Surprisingly, we also found unexpected and pronounced astrocyte pathology. DM1 astrocytes exhibited reduced ramification and impaired cell adhesion, and had a strong negative impact on neuritogenesis. In conclusion, my results demonstrate for the first time that DM1 brain dysfunction is mediated by neuronal and non-neuronal mechanisms. My results are important to the understanding of the molecular and cellular etiology of cognitive intellectual impairment in this devastating disease, and for the design of future therapies.
Marion Pellen
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch. France
Thesis title: Role of the beta-amyloid peptide precurcor gene under physiological conditions and in Trisomy 21 in the Rat
Thesis advisor: Hérault Yann
Co-advisor: Cassel Jean-Christophe
The β-Amyloid Precursor Protein (APP) is a transmembrane glycoprotein expressed ubiquitously. This protein has many physiological functions, is involved mainly in proliferation, differentiation and cell migration and synaptic plasticity. However, the mechanisms underlying these functions are poorly known. Indeed, APP is target of many studies for its involvement in Alzheimer’s disease (AD), where the APP gene presents numerous mutations. Moreover, the simple duplication of this gene, located on chromosome 21, is sufficient to induce the development of AD. Thus, people with Down Syndrome (DS) who have 3 copies of the APP gene, show higher risk of developing AD. However, the pathophysiology of AD in the context of DS is unknown. The purpose of this thesis was first, to study the physiological role of APP during aging and second, to identify the mechanisms of AD in the context of DS by using new rats models.