Striatal Induction and Spread of the Huntington's Disease Protein: A Novel Rhes Route

The CAG/CAA expansion encoding polyQ huntingtin (mutant huntingtin [mHTT]) causes Huntington's disease (HD), which is characterized by atrophy and loss of striatal medium spiny neurons (MSNs), which are preceded by neuropathological alterations in the cortex. Previous studies have shown that mHTT can spread in the brain, but the mechanisms involved in the stereotyped degeneration and dysfunction of the neurons from the striatum to the cortex remain unclear. In this study, we found that the mHTT expression initially restricted in the striatum later spread to the cortical regions in mouse brains. Such transmission was diminished in mice that lacked the striatal-enriched protein Ras-homolog enriched in the striatum (Rhes). Rhes restricted to MSNs was also found in the cortical layers of the brain, indicating a new transmission route for the Rhes protein to the brain. Mechanistically, Rhes promotes such transmission via a direct cell-to-cell contact mediated by tunneling nanotubes (TNTs), the membranous protrusions that enable the transfer of mHTT, Rhes, and other vesicular cargoes. These transmission patterns suggest that Rhes and mHTT are likely co-transported in the brain using TNT-like cell-to-cell contacts. On the basis of these new results, a perspective is presented in this review: Rhes may ignite the mHTT transmission from the striatum that may coincide with HD onset and disease progression through an anatomically connected striato-cortical retrograde route.