Progressive alterations in polysomal architecture in a mouse model of Huntington’s disease

Given their highly polarized morphology and functional singularity, neurons require precise spatial and temporal control of protein synthesis. Alterations in protein translation have been implicated in the development and progression of a wide range of neurological and neurodegenerative disorders, including Huntington’s disease (HD). We examined the architecture of polysomes in their native brain context by performing 3D electron tomography of striatal tissue from the zQ175 knock-in mouse model of HD. Results revealed progressive remodelling towards a more compacted polysomal architecture, an effect that coincided with the emergence and progression of HD related symptoms. This aberrant architecture is compatible with ribosome stalling phenomena. In fact, we also detected an increase in the striatal expression of the stalling relief factor EIF5A2. Polysomal sedimentation gradients showed a significant increase in the accumulation of free 40S ribosomal subunits in zQ175 striatal samples. Together, these findings indicate that changes in the architecture of the protein synthesis machinery may underlie translational alterations associated with HD, thus opening new avenues for understanding the progression of this disease.