Laurence Colleaux & Vincent Cantagrel

Molecular and pathophysiological bases of cognitive disorders

Laurence Colleaux & Vincent Cantagrel
  • Anne Philippe 
  • Lam Son Nguyen
  • Valérie Malan
  • Vincent Cantagrel
  • Laurence Colleaux
  • Nathalie Boddaert
  • Julien Fregeac
  • Daniel Medina Cano
  • Florine Verny
  • Karine Siquier-Pernet

Molecular and pathophysiological bases of cognitive disorders

The term intellectual disabilities (ID) correspond to a large and extremely heterogeneous collection of childhood conditions that are all characterized by significant limitations in both intellectual functioning and adaptive behavior. The causes of ID are diverse and include environmental factors, teratogens, abnormal chromosome number or structure, genetic defects and metabolic diseases. However, 25-40% of the severe IDs and most mild forms remain unexplained. With a prevalence of 2% of the population, ID accounts for 10% of the total health care cost in most Western countries far more than cancer or cardiovascular diseases.
Understanding the biological bases of these conditions is thus a major medical and socio-economical challenge. Our project aims to decipher the molecular defects underlying cognitive disorders and to elucidate the pathophysiological mechanisms leading to cognitive impairment.


1. Identify the molecular bases of unexplained ID conditions
Using state-of-the-art genetic and genomics technologies, we identified more than 40 chromosomal imbalances
and 20 disease-causing mutations responsible for ID. Our most important scientific accomplishments include (i) the identification of neurotrypsin as the first non-syndromic autosomal recessive ID gene, linking impaired brain plasticity and defects in extracellular proteolytic activity at the synapse; (ii) the identification of the TUSC3 gene, emphasizing the crucial role of N-glycosylation in higher brain function; (iii) the identification of the MED23 gene, highlighting the key role of the Mediator in brain development and functioning and suggesting that altered IEG expression might be a molecular hallmark of cognitive deficit; (iv) the demonstration that members of the Drosophila Behaviour Human Splicing (DBHS) protein family play a key role in inhibitory synapse biology.

2. Evaluate the role of epigenomic variations in the etiology of ASD
Autism spectrum disorder (ASD) is a neurodevelopmental disease caused by an interaction between genetic vulnerability and environmental factors. MicroRNAs (miRs) have emerged as key post-transcriptional regulators and are involved in multiple aspects of brain development and connectivity. Profiling miRNAs in olfactory mucosal stem cells (OMSC), we identified a molecular signature of four miRNAs (miR-146a, miR-221, miR-654-5p and miR-656) dysregulated in ASD. We are currently developing cellular and mouse models to understand how miRNAs expression deregulation alters brain development and synaptic functions

3. Understand the role of ID gene products in brain development
To evaluate the functional impact of the genomic variants identified in the previous step and to study underlying mechanisms of observed phenotypes several complementary approaches based on yeast models, CRISPR-Cas9 genome editing system in human neuronal stem cells and organisms like zebrafish or mouse are used. Our results already highlighted unforeseeable pathophysiological mechanisms such as impaired extracellular proteolytic activity at the synapse or altered immediate early gene expression. They also open novel therapeutic avenues aiming to enhance possibilities of healthcare for these patients such as new pharmacological approach of MMPSI based on inhibition of constitutively activated KCNT1 channel or new strategies based on the manipulation of miRNAs expression in the field of ASD.

4. Identify the molecular causes of developmental cerebellar disorders with ID
Cerebellar defects are well known to cause imbalance and poor coordination. However, over the last decade, clinical and neuropsychological investigations highlighted the important role of the cerebellum in the acquisition of higher-order cognitive and affective skills. A better understanding of human cerebellum development should help to understand its role in cognition. We currently use exome sequencing in patients from Necker hospital or from the Middle East to identify new genes involved in these disorders and we study the effect of the identified variants using cell, fish or mouse models.
5. Characterize the physiopathological mechanisms involved in the neurological symptoms caused by a defect in protein N-glycosylation
The disruption of protein N-glycosylation is responsible of a group of genetic diseases frequently associated with ID and cerebellar atrophy/hypoplasia. The reason why the central nervous system and mostly the cerebellum are especially sensitive to this defect is totally unknown. This project aim is to identify the cellular and biochemical targets involved in these diseases using a conditional knockout mouse model for the Srd5a3 gene.

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