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

Abstract

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.

Tunneling Nanotube: An Enticing Cell–Cell Communication in the Nervous System

“…As discussed above, we identified the involvement of Rhes in the formation of TNTs [2,3,22,35,97]. While Rhes is self-transported via TNTs (Figures 1 and 2; Video S1), it also facilitates the transport of the poly-Q expanded mHTT protein that is associated with HD [23].…”

“…Our recent research findings suggest that the Rhes protein, functioning as a multifunctional GTPase resembling SUMO E3 ligase, plays a vital role in the formation of TNTs and the facilitation of mHTT transportation between striatal medium spiny neurons (MSNs) and the cortex; the brain circuit is known to be highly vulnerable to degeneration in HD [2,4,22,23]. This transport of mHTT via Rhes is partly dependent on the SUMO posttranslational modification of mHTT [2][3][4]23,70].…”

“…Intercellular communication in the nervous system plays a critical role in coordinating essential functions. TNTs have recently emerged as fascinating avenues of intercellular communication [1][2][3][4]. TNTs are membranous cell-cell communication structures that were first reported in neuronal phaeochromocytoma 12 (PC12) cells [5].…”

“…TNTs have received much attention due to their connection to neurodegenerative diseases. Studies have implicated TNTs in diseases such as Alzheimer's disease (AD), Creutzfeldt-Jakob disease, Huntington's disease (HD), and Parkinson's disease (PD) [3,4,11,[19][20][21][22][23][24]. The spread of disease-causing pathological proteins between neurons through TNTs can contribute to the propagation of disease across different brain areas [21,25].…”

“…This review article, based on our recent works on TNTs [2][3][4]22,23,35], will concentrate on studies examining the role of TNTs in the nervous system and their involvement in neurodegenerative diseases. Neurons, which are distinct from other cells, possess specialized abilities for long-range communication through electrical and chemical signals.…”