The role of translational dysregulation in sensory neurons in mediating tactile hypersensitivity in neurodevelopmental disorders
Sensory dysfunction is prominent in sporadic and syndromic forms of autism, significantly impairing the quality of life of affected individuals. Tactile hypersensitivity is often observed in patients with Autism Spectrum Disorder (ASD) and in ASD animal models, yet its mechanistic underpinnings are not well understood. In several single-gene disorders, which are co-diagnosed with high-rates of autism and are frequently accompanied by mechanical hypersensitivity, there is increased activity of the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 is a serine/threonine kinase that controls mRNA translation initiation. We found that selective stimulation of translation initiation in sensory neurons, via deletion of the mTORC1 downstream effector and translational repressor 4E-BP1, leads to tactile hypersensitivity. Sensory neuron-specific translational profiling revealed that translation of mitochondrial genes is preferentially affected in 4E-BP1-ablated neurons. We hypothesise that activation of mTORC1/4E-BP1-dependent translation of specific mRNAs is a key mechanism for the regulation of sensory neuron mechanical sensitivity and underlies tactile hypersenitivity in neurodevelopmental disorders such as ASD. In this project, we propose to study the molecular mechanisms by which the activation of mTORC1/4E-BP1 causes tactile hypersensitivity and develop treatment strategies to reverse this phenotype using rodent models and human pluripotent cell-derived sensory neurons.
Stem cells and neural differentiation/cell therapy, Electrophisiological approaches, Behavioural methodologies, omics approaches, Animal studies, protein synthesis; mechanoreceptors; tactile sensing; Autism Spectrum Disorders
2021 - 2024
Christos Gkogkas (Coordinator)