Rhes Tunnels: A Radical New Way of Communication in the Brain's Striatum?

Subramaniam, Srinivasa

doi:10.1002/bies.201900231

Cited by 14 publications

(24 citation statements)

References 155 publications

(124 reference statements)

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“…However, the mechanisms that promotes striatal damage remain unclear, as do the mechanisms via which cGAS activation in HD regulates striatal vulnerability. We speculate that in the striatum, Rhes, a GTPase/SUMOE3-like protein, which increases mHTT solubility and promotes cell-to-cell transport of mHTT via tunneling-nanotube–like membrane protrusions, might participate in cGAS activity and propagate inflammatory and autophagy responses via intercellular signaling ( 99 – 104 ).…”

Section: Discussionmentioning

confidence: 99%

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Sharma

Sumitha

Shahani

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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106

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Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine of huntingtin (mHTT). mHTT is ubiquitously present, but it induces noticeable damage to the brain’s striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling revealed that thecGASmRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. Moreover, the protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5andCxcl10) are increased in HD striatum. Depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy in HD cells. In contrast, reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Ribosome profiling also revealed thatLC3AandLC3B, the two major autophagy initiators, show altered ribosome occupancy in HD cells. We also detected the presence of numerous micronuclei, which are known to induce cGAS, in the cytoplasm of neurons derived from human HD embryonic stem cells. Collectively, our results indicate that cGAS is up-regulated in HD and mediates inflammatory and autophagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.

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Section: Discussionmentioning

confidence: 99%

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Sharma

Sumitha

Shahani

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

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“…Another outcome induced by TNT-dependent communication is the spread of infectious and neurodegenerative substances [ 23 , 27 , 97 ]. The first evidence provided by the group of Davis showed that membrane nanotubes physically connecting T cells acted as a novel route for HIV-1 transmission [ 21 ].…”

Section: Versatile Functions Of Tntsmentioning

confidence: 99%

Opportunities and Challenges in Tunneling Nanotubes Research: How Far from Clinical Application?

Han

Wang

2021

IJMS

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Tunneling nanotubes (TNTs) are recognized long membrane nanotubes connecting distance cells. In the last decade, growing evidence has shown that these subcellular structures mediate the specific transfer of cellular materials, pathogens, and electrical signals between cells. As intercellular bridges, they play a unique role in embryonic development, collective cell migration, injured cell recovery, cancer treatment resistance, and pathogen propagation. Although TNTs have been considered as potential drug targets for treatment, there is still a long way to go to translate the research findings into clinical practice. Herein, we emphasize the heterogeneous nature of TNTs by systemically summarizing the current knowledge on their morphology, structure, and biogenesis in different types of cells. Furthermore, we address the communication efficiency and biological outcomes of TNT-dependent transport related to diseases. Finally, we discuss the opportunities and challenges of TNTs as an exciting therapeutic approach by focusing on the development of efficient and safe drugs targeting TNTs.

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“…Impaired autophagy is a wellestablished hallmark of neurodegenerative diseases, including tauopathies [2,23,26,32]. Rhes has an established role in autophagy modulation [10,19,25], including its role in forming tunneling nanotube-like protrusions [28]. These protrusions are thought to facilitate the selective transfer of membrane vesicles and organelles, including lysosomes and endosomes, between cells.…”

Section: Discussionmentioning

confidence: 99%

Patterns of neuronal Rhes as a novel hallmark of tauopathies

et al. 2021

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The farnesyltransferase inhibitor, Lonafarnib, reduces tau inclusions and associated atrophy in familial tauopathy models through activation of autophagy, mediated by the inhibition of farnesylation of the Ras GTPase, Rhes. While hinting at a role of Rhes in tau aggregation, it is unclear how translatable these results are for sporadic forms of tauopathy. We examined histological slides of allocortex and neocortex from multiple postmortem cases in five different tauopathies, FTLD-TDP, and healthy controls using immunofluorescence for Rhes, several tau post-translational modifications, and phospho-TDP-43. Single nucleus RNA data suggest that Rhes is found in all cortical neuron subpopulations but not in glia. Histologic investigation showed that nearly all neurons in control brains display a pattern of diffuse cytoplasmic Rhes positivity. However, in the presence of abnormal tau, but not abnormal TDP-43, the patterns of neuronal cytoplasmic Rhes tend to present as either punctiform or entirely absent. This observation reinforces the relevance of findings that link Rhes changes and tau pathology from the in vivo and in vitro models of tauopathy. The results here support a potential clinical application of Lonafarnib to tauopathies.

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Rhes Tunnels: A Radical New Way of Communication in the Brain's Striatum?

Cited by 14 publications

References 155 publications

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Opportunities and Challenges in Tunneling Nanotubes Research: How Far from Clinical Application?

Patterns of neuronal Rhes as a novel hallmark of tauopathies

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