Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease

Caron, Nicholas S.; Banos, Raul; Yanick, Christopher; Aly, Amirah E-E; Byrne, Lauren M.; Smith, Ethan D.; Xie, Yuanyun; Smith, Stephen; Potluri, Nalini; Black, Hailey Findlay; Casal, Lorenzo; Ko, Seung‐Hyun; Cheung, Daphne Sze Ki; Kim, Hyeongju; Seong, Ihn Sik; Wild, Edward J.; Song, Ji‐Joon; Hayden, Michael R.; Southwell, Amber L.

doi:10.1523/jneurosci.1865-20.2020

Cited by 43 publications

(34 citation statements)

References 58 publications

(78 reference statements)

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“…We found that HTTEx1Q72-mCherry transmission is elevated by neuronal depolarization, while preventing neuronal presynaptic release results in decreased transmission. This, together with previously published data on Aβ, Tau and mHTTEx1, strongly suggest that transmission occurs across functional synapses and is regulated by at least presynaptic activity [14][15][16][17]51 . In addition, a constitutive secretion is supported by our observation thathiPSC clones with higher HTTEx1Q72 expression levels showed more transmission to muscle (~15-fold increase in HTTEx1Q72-mCherry puncta between myotubes cultured with clones #72 and #75).…”

Section: Discussionsupporting

confidence: 81%

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Dinamarca¹,

Colombo

Brykczynska

et al. 2021

Preprint

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A potential explanation for the spatiotemporal accumulation of pathological lesions in the brain of patients with neurodegenerative protein misfolding diseases (PMDs) is cell-to-cell transmission of aggregation-prone, misfolded proteins. Little is known about central to peripheral transmission and its contribution to pathology. We show that transmission of Huntington’s disease- (HD-) associated mutant HTT exon 1 (mHTTEx1) occurs across the neuromuscular junctions in human iPSC cultures and in vivo in wild-type mice. We found that transmission is an active and dynamic process, that happens prior to aggregate formation and is regulated by synaptic activity. Furthermore, we find that transmitted mHTTEx1 causes HD-relevant pathology at a molecular and functional level in human muscle cells, even in the presence of ubiquitous expression mHTTEx1. With this work we uncover a casual-link between mHTTEx1 synaptic transmission and pathology, highlighting the therapeutic potential in blocking toxic protein transmission in PMDs.

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Section: Discussionsupporting

confidence: 81%

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Dinamarca¹,

Colombo

Brykczynska

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…We found that HTTEx1Q72-mCherry transmission is elevated by neuronal depolarization, while preventing neuronal presynaptic release results in decreased transmission. This, together with previously published data on Aβ, Tau and mHTTEx1, strongly suggest that transmission occurs across functional synapses and is regulated by at least presynaptic activity [14][15][16][17]51 . In addition, a constitutive secretion is supported by our observation that hiPSC clones with higher HTTEx1Q72 expression levels showed more transmission to muscle (~15-fold increase in HTTEx1Q72-mCherry puncta between myotubes cultured with clones #72 and #75).…”

Section: Discussionsupporting

confidence: 81%

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Ceballos

Colombo

Brykczynska

et al. 2021

Preprint

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Skeletal muscle dysfunction, wasting and synaptic pathology is a hallmark of Huntingtons disease (HD). Similar as for the nervous system the pathological lesions and clinical symptoms progressively worsen with disease coarse. Cell-to-cell transmission of toxic mutant huntingtin (mHTT) has been shown to occur and could be a potential explanation for the progressive accumulation of pathological lesions and clinical symptoms in time. However, the mechanism and contribution of mHTT cell-to-cell transmission to pathology in an environment of ubiquitous expression of the mutant protein is not well understood. Here, we show that the HD-associated mHTT exon 1 (mHTTEx1) is transmitted from human induced pluripotent stem cell- (hiPSC-) derived motor neurons (MNs) to isogenic hiPSC-derived myotubes across functionally active neuromuscular junctions (NMJ) and in vivo in wild-type mice from the M1 motor cortex to spinal MNs and skeletal muscles. Increased synaptic connectivity and activity enhances transmission. Also, our data reveals that transmission happens prior to aggregate formation and that aggregation occurs progressively with continuous transmission across weeks at the myotube surface. Furthermore, we provide evidence that mHTTEx1 derived from MNs causes defragmentation of mitochondria and exacerbates nuclear aggregation, the latter in the presence of myotube autonomous mHTTEx1. Finally, we find that mHTTEx1 transmission results in decreased myotube contractions, in contrast myotube autonomous expression causes a hyperexcitable-like phenotype. Altogether, our data suggests that mHTTEx1 neuromuscular transmission contributes to skeletal muscle dysfunction in HD, via continuous transmission of the toxic protein already at early preclinical stages of HD and thereby contributes to an increasing accumulation of toxic protein in skeletal muscle, eventually leading to a highly-selective phenotype resulting in a decline of skeletal muscle function. Since multiple studies support a role of synaptic transmission of diverse misfolded proteins, including tau in Alzheimers, alpha-synuclein in Parkinsons, mHTT in HD, tdp-43 in Amyotrophic lateral sclerosis and frontotemporal lobar dementia, in the central nervous system, this process likely represents a common synaptic-linked pathobiological pathway for most neurodegenerative protein misfolding diseases.

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“…NfL has also been found in higher concentrations in plasma and CSF of HD and pre-HD patients and is thought to be related to neuronal cell death [ 104 ]. However, since acute neurotoxicity leads to transient increases in CSF mtHTT [ 105 , 106 ], which is known to predominantly originate from neural tissues of the CNS [ 105 ], the concomitant reduction in CSF mtHTT suggests that the increase in CSF NfL may not necessarily be tied to cell death. Considering that HTT is mostly perinuclear, while NfL is found throughout processes, both would be released by cell death, while NfL could be preferentially released by changes affecting cell processes, such as de-arborization and loss of connectivity.…”

Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic

Rook

2022

BioDrugs

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Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease

Abstract: and Loqus23. All honoraria for these engagements were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College, London. MRH currently serves on the public boards of Ionis Pharmaceuticals, Xenon Pharmaceuticals, Aurinia Pharmaceuticals and 89bio.

Cited by 43 publications

References 58 publications

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Transmission-selective muscle pathology induced by active propagation of mutant huntingtin across the human neuromuscular synapse

Antisense Oligonucleotide Therapy: From Design to the Huntington Disease Clinic

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