Use of adeno-associated virus-mediated delivery of mutant huntingtin to study the spreading capacity of the protein in mice and non-human primates

Maxan, Alexander; Sciacca, Giacomo; Alpaugh, Melanie; Zhu, Tong; Breger, Ludivine S.; Dehay, Benjamin; Zhang, Ling; Qin, Chuan; Cisbani, Giulia; Masnata, Maria; Salem, Shireen; Lacroix, Steve; Oueslati, Abid; Bézard, Erwan; Cicchetti, Francesca

doi:10.1016/j.nbd.2020.104951

Cited by 14 publications

(7 citation statements)

References 49 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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show abstract

“…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%

Targeting Tau to Treat Clinical Features of Huntington's Disease

et al. 2020

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“…Currently, it remains unclear whether different types of mHTT aggregate species play a role in the observed disease process in zQ175 KI mice. Previous evidence has been obtained that N-terminal mHTT exon-1 (mHTTex1) fragments spontaneously self-assemble into stable β-sheet fibrillar structures in vitro and in vivo ( Scherzinger et al, 1997 , 1999 ; Waelter et al, 2001 ) and are also able to spread from cell to cell ( Babcock and Ganetzky, 2015 ; Maxan et al, 2020 ). Whether such seeding- and spreading-competent structures are directly involved in pathogenesis is still a matter of debate ( Hoffner and Djian, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington’s Disease Knock-in Mice

et al. 2021

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The deposition of mutant huntingtin (mHTT) protein aggregates in neurons of patients is a pathological hallmark of Huntington’s disease (HD). Previous investigations in cell-free and cell-based disease models showed mHTT exon-1 (mHTTex1) fragments with pathogenic polyglutamine (polyQ) tracts (>40 glutamines) to self-assemble into highly stable, β-sheet-rich protein aggregates with a fibrillar morphology. HD knock-in mouse models have not been extensively studied with regard to mHTT aggregation. They endogenously produce full-length mHTT with a pathogenic polyQ tract as well as mHTTex1 fragments. Here, we demonstrate that seeding-competent, fibrillar mHTT aggregates can be readily detected in brains of zQ175 knock-in HD mice. To do this, we applied a highly sensitive FRET-based protein amplification assay that is capable of detecting seeding-competent mHTT aggregate species down to the femtomolar range. Furthermore, we show that fibrillar structures with an average length of ∼200 nm can be enriched with aggregate-specific mouse and human antibodies from zQ175 mouse brain extracts through immunoprecipitations, confirming that such structures are formed in vivo. Together these studies indicate that small, fibrillar, seeding-competent mHTT structures are prominent aggregate species in brains of zQ175 mice.

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Use of adeno-associated virus-mediated delivery of mutant huntingtin to study the spreading capacity of the protein in mice and non-human primates

Cited by 14 publications

References 49 publications

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

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

Targeting Tau to Treat Clinical Features of Huntington's Disease

Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington’s Disease Knock-in Mice

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