A012 Mutant huntingtin causes early transcriptional modifications in the developing brain

<h3></h3> Huntington disease (HD) is an autosomal dominant neurological disease caused by an increased number of CAG repeats in exon 1 of the Huntingtin gene (HTT). Although symptoms typically manifest in adulthood, early cellular alterations occur during brain development.¹ Our team identified, via RNA sequencing, transcriptional changes at 13 gestational weeks in the cortex of human fetuses carrying the mutation, affecting pathways involved in the regulation of axonal guidance and cytoskeletal dynamics. Evidence of axonal growth defects in HD was previously documented in mice, where cytoskeleton disorganization in newborn cortical neurons leads to a reduction of callosal projections.² Here, we focused on the Netrin 1 pathway, which we found significantly altered in HD compared to control fetuses. In the developing cortex of the HdhQ140 mouse model, we demonstrated gene deregulations of components of the netrin 1 pathway using RNAscope. In favor of this, a single nuclei RNA sequencing done in the same brain structure revealed a major modification of actin genes, which are known to be modified by netrin 1 signals.³ We are currently establishing a cellular model involving treatment with exogenous Netrin 1, which we will combine to RNA sequencing experiments on total cortices from embryogenesis to post-natal stages, to decipher the mechanisms of these modifications. This study should lead to progress in understanding the mechanisms underlying the mutation, placing the deregulation of axonal growth genes as a central element contributing to neurodevelopmental cellular alterations in HD. <h3>References</h3> Barnat M, <i>et al</i>. Huntington’s disease alters human neurodevelopment. <i>Science</i> 2020. Capizzi M, <i>et al</i>. Developmental defects in Huntington’s disease show that axonal growth and microtubule reorganization require NUMA1. <i>Neuron</i> 2021. Dent EW, <i>et al</i>. The growth cone cytoskeleton in axon outgrowth and guidance. <i>Cold Spring Harb Perspect Biol</i> 2011.