Home » Collaborative Research » Functional implications of pathogenic mutations in synaptic proteins

Functional implications of pathogenic mutations in synaptic proteins

Principal investigator:

Most neurodevelopmental disorders (NDDs) have a strong genetic component. Until recently, causal genes had primarily been found in the context of Intellectual Disability (ID). Although twin studies indicate that NDDs such as attention deficit hyperactivity disorder (ADHD) or autism spectrum disorders (ASD) have an important genetic background, classical genetic studies have failed to identify genes with high penetrance in these conditions.

Recent developments in DNA analysis and sequencing, such as next-generation sequencing, SNP arrays, exome sequencing or analysis of copy number variations (CNVs), allow to study the whole genome of large cohorts of affected individuals, enabling the analysis of CNS disorders with highly heterogeneous genetic etiology.

Interestingly, many of the genes identified in the context of NDDs are involved in synaptic function pointing towards a synaptic dysfunction as an important contributing factor in many of these disorders. It is therefore important to understand how these mutations alter normal synaptic biology, specially at the molecular level. Deciphering the molecular pathology of these disorders should path the way for future therapeutical approaches.

Related publications

  • Synaptic proteomics as a means to identify the molecular basis of mental illness: Are we getting there?Reig-Viader R, Sindreu C and Bayés À.

    Synapses are centrally involved in many brain disorders, particularly in psychiatric and neurodevelopmental ones. However, our current understanding of the proteomic alterations affecting synaptic performance in the majority of mental illnesses is limited. As a result, novel pharmacotherapies with improved neurological efficacy have been scarce over the past decades.

  • DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors.Grau C, Arató K, Fernández-Fernández J, Valderrama A, Sindreu C, Fillat C, Ferrer I, De la Luna S and Altafaj X.

    N-methyl-D-aspartate glutamate receptors (NMDARs) play a pivotal role in neural development and synaptic plasticity, as well as in neurological disease. Since NMDARs exert their function at the cell surface, their density in the plasma membrane is finely tuned by a plethora of molecules that regulate their production, trafficking, docking and internalization in response to external stimuli.

  • Glutamate receptor mutations in psychiatric and neurodevelopmental disordersSoto D, Altafaj X, Sindreu C and Bayés À.

    Alterations in glutamatergic neurotransmission have long been associated with psychiatric and neurodevelopmental disorders (PNDD), but only recent advances in high-throughput DNA sequencing have allowed interrogation of the prevalence of mutations in glutamate receptors (GluR) among afflicted individuals.