Striatal Communication Via The Tunneling Nanotubes

When cells came into existence millions of years ago, they had a better chance of survival if they could communicate with one another. Cellular protrusions like tunneling nanotubes (TNTs) may have emerged as a secure and efficient form of direct communications.

We recently discovered that Rhes (266 aa), which consists of small GTPase (1-171 aa) and SUMO E3-like domain (171-266 aa), play an essential role in the formation of TNT-like protrusions in cultured neuronal cell lines and primary striatal neurons (See Video 1 and Video 2). Rhes is highly expressed in the medium spiny neurons (MSNs) and cholinergic interneurons in the striatum; it is also expressed to some extent in cortex and the hippocampus]. We ascribed several new roles for Rhes in the striatum in PD, inhibitory motor activity, and HD, which is consistent with independent reports. We found Rhes promotes posttranslational modification of mHTT with small ubiquitin-like modifier (SUMO) and promotes cellular toxicity. Rhes also plays a critical role in mutant, tau-mediated pathology. In addition, a rare, highly conserved de novo mutation (R57H) in Rhes was detected in twins diagnosed on the autistic spectrum. Despite these studies, the mechanisms by which Rhes regulates distinct striatal functions remain unclear.
Recently, we found that Rhes travels from cell to cell as vesicular puncta from one cell (donor) to another cell (acceptor) via the TNT-like cellular protrusion “Rhes tunnel” (Fig. 1A, white arrow)[45]. Rhes vesicular puncta (blue arrow) do not directly enter the lumen of the acceptor cell; rather, they slide along the plasma membrane (arrowhead) before entering the cytoplasm of the acceptor neuronal cells (Fig. 1A). Scanning electron microscopy (SEM) revealed Rhes tunnels appeared to connect two cells, and their surface showed a seamless transition with the surface of connected cells (Fig. 1B). Furthermore, we discovered that lysosomes, endosomes, and mHTT, the genetic cause of HD, are readily transported in Rhes tunnels[45]. The lipid modification domain of Rhes (C263) and SUMO E3 ligase domain contributes to the formation of the TNT-like Rhes tunnel and cargo transport[45].

Rhes travels from neuron to neuron in vitro and in vivo

To discover whether Rhes can be transported between neurons in vivo, we took advantage of the well-characterized Cre-recombinase system. We used D1RCre; D2REGFP mice and selectively expressed “Cre-On” RFP or RFP-Rhes in D1RCre and found numerous RFP-Rhes, but not RFP-alone, signals within D2REGFP neurons in the striatum (Fig. 1C). Collectively, these data indicated that Rhes travels between neurons in cultured cells and from the D1R neurons to the D2R neurons in vivo. To the best of our knowledge, Rhes is the first striatal-enriched protein demonstrated to travel between neurons in vitro and in vivo.

Outstanding questions

Our study, along with an increasing body of other studies, underlines that TNT-like protrusions may have a major role in intercellular protein transport; however, their role in the brain biology or disease remains unknown. Identifying the mechanisms and in vivo functions of Rhes transport has the potential to transform our understanding of striatal neuron signaling and its abnormalities associated with striatal disease.