Evidence for the spread of human-derived mutant huntingtin protein in mice and non-human primates

Gosset, Philippe; Maxan, Alexander; Alpaugh, Melanie; Breger, Ludivine S.; Dehay, Benjamin; Zhu, Tong; Zhang, Ling; Qin, Chuan; Cisbani, Giulia; Fortin, Nadia; Vonsattel, Jean‐Paul; Lacroix, Steve; Oueslati, Abid; Bézard, Erwan; Cicchetti, Francesca

doi:10.1016/j.nbd.2020.104941

Cited by 14 publications

(9 citation statements)

References 40 publications

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“…Several studies have indicated that mHTT has prion-like properties that may contribute to its cell-to-cell transmission (83,86,(90)(91)(92). Previous work showed that TNTs may serve as a route for the transport of prion-like protein between cultured cells (93,94).…”

Section: Discussionmentioning

confidence: 99%

Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain

Ramírez-Jarquín

Sharma

Shahani

et al. 2021

Preprint

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Rhes (RASD2) is a thyroid hormone-induced gene that regulates striatal motor activity and promotes neurodegeneration in Huntington disease (HD) and tauopathy. Previously, we showed that Rhes moves between cultured striatal neurons and transports the HD protein, polyglutamine-expanded huntingtin (mHTT) via tunneling nanotube (TNT)-like membranous protrusions. However, similar intercellular Rhes transport has not yet been demonstrated in the intact brain. Here, we report that Rhes induces TNT-like protrusions in the striatal medium spiny neurons (MSNs) and transported between dopamine-1 receptor (D1R)-MSNs and D2R-MSNs of intact striatum and organotypic brain slices. Notably, mHTT is robustly transported within the striatum and from the striatum to the cortical areas in the brain, and Rhes deletion diminishes such transport. Moreover, we also found transport of Rhes to the cortical regions following restricted expression in the MSNs of the striatum. Thus, Rhes is a first striatum-enriched protein demonstrated to move and transport mHTT between neurons and brain regions, providing new insights on interneuronal protein transport in the brain.

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Section: Discussionmentioning

confidence: 99%

Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain

Ramírez-Jarquín

Sharma

Shahani

et al. 2021

Preprint

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“…Loss of proteostasis is increasingly appreciated not only as a component of age-related neurodegeneration but also as a driver of skeletal muscle aging (sarcopenia) and age-related myopathies in Drosophila, mice, and humans [152,155,229,230]. In this framework, it has been proposed that aggregation-prone pathogenic proteins could be released by skeletal muscle and other peripheral tissues and subsequently be uptaken by cells in the CNS, where they could contribute to derange protein quality control and to promote neurodegeneration [8,231,232]. A study in C. elegans has found some evidence for inter-tissue transmission of pathogenic huntingtin between skeletal muscle and neurons and such myofiber-to-neuron spreading of huntingtin led to neurodegeneration and reduced lifespan [232].…”

Section: U N C O R R E C T E D a U T H O R P R O O Fmentioning

confidence: 99%

Muscle-to-Brain Signaling Via Myokines and Myometabolites

Rai

Demontis

2022

BPL

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Skeletal muscle health and function are important determinants of systemic metabolic homeostasis and organism-wide responses, including disease outcome. While it is well known that exercise protects the central nervous system (CNS) from aging and disease, only recently this has been found to depend on the endocrine capacity of skeletal muscle. Here, we review muscle-secreted growth factors and cytokines (myokines), metabolites (myometabolites), and other unconventional signals (e.g. bioactive lipid species, enzymes, and exosomes) that mediate muscle-brain and muscle-retina communication and neuroprotection in response to exercise and associated processes, such as the muscle unfolded protein response and metabolic stress. In addition to impacting proteostasis, neurogenesis, and cognitive functions, muscle-brain signaling influences complex brain-dependent behaviors, such as depression, sleeping patterns, and biosynthesis of neurotransmitters. Moreover, myokine signaling adapts feeding behavior to meet the energy demands of skeletal muscle. Contrary to protective myokines induced by exercise and associated signaling pathways, inactivity and muscle wasting may derange myokine expression and secretion and in turn compromise CNS function. We propose that tailoring muscle-to-CNS signaling by modulating myokines and myometabolites may combat age-related neurodegeneration and brain diseases that are influenced by systemic signals.

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“…Furthermore, administration of tau-targeting antibodies by injection is a straightforward and safe procedure (207). Based on the concept that mHTT can propagate between cells and template pathology in a prion-like fashion, active and passive immunization strategies targeting extracellular mHTT are attracting interest (215)(216)(217)(218)(219)(220)(221)(222) [extensively reviewed in (213)], and could be tested in parallel to a tau, or mHTT/tau combined immunization. Furthermore, halting accumulation and propagation of pathogenic proteins in HD patients at early stages of the disease, before they are afflicted by neurodegeneration and cognitive dysfunction, may provide the most effective protection.…”

Section: Views On Tau Immunotherapiesmentioning

confidence: 99%