Loss of huntingtin function slows synaptic vesicle endocytosis in striatal neurons from the httQ140/Q140 mouse model of Huntington's disease

McAdam, Robyn; Morton, Andrew; Gordon, Sarah; Alterman, Julia F.; Khvorova, Anastasia; Cousin, Michael A.; Smillie, Karen J.

doi:10.1016/j.nbd.2019.104637

Cited by 26 publications

(19 citation statements)

References 61 publications

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“…Together, the aforementioned studies suggest that wtHTT loss of function (LOF) may disrupt presynaptic homeostasis by impairing clathrin-mediated SV recycling. A direct role of wtHTT in SV endocytosis was demonstrated recently when self-deliverable, cholesterol-conjugated siRNAs were used to knock down wtHTT expression in cultured neurons ( McAdam et al, 2020 ). In this study, wtHTT levels were reduced to approximately 20% of that observed in control neurons, and the fluorescent reporter synaptophysin-pHluorin (syp-pH) was used to quantify the rate of SV recycling.…”

Section: Huntingtin and The Presynapsementioning

confidence: 89%

“…Together, these data demonstrate a clear role for wtHTT as a positive regulator of SV recycling. Interestingly, the recycling rate was unaffected in cultured hippocampal neurons following wtHTT knockdown, suggesting that the consequences of wtHTT reduction on synaptic function varies in a region-dependent manner ( McAdam et al, 2020 ).…”

Section: Huntingtin and The Presynapsementioning

confidence: 99%

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Huntingtin and the Synapse

Barron

Hurley

Parsons

2021

Front. Cell. Neurosci.

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Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. However, many of these treatment strategies are non-selective in that they cannot differentiate between non-pathogenic wild type HTT (wtHTT) and the mHTT variant. As HD patients are already born with decreased levels of wtHTT, these genetic therapies may result in critically low levels of wtHTT. The consequence of wtHTT reduction in the adult brain is currently under debate, and here we argue that wtHTT loss is not well-tolerated at the synaptic level. Synaptic dysfunction is an extremely sensitive measure of subsequent cell death, and is known to precede neurodegeneration in numerous brain diseases including HD. The present review focuses on the prominent role of wtHTT at the synapse and considers the consequences of wtHTT loss on both pre- and postsynaptic function. We discuss how wtHTT is implicated in virtually all major facets of synaptic neurotransmission including anterograde and retrograde transport of proteins to/from terminal buttons and dendrites, neurotransmitter release, endocytic vesicle recycling, and postsynaptic receptor localization and recycling. We conclude that wtHTT presence is essential for proper synaptic function.

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Section: Huntingtin and The Presynapsementioning

confidence: 89%

Section: Huntingtin and The Presynapsementioning

confidence: 99%

Huntingtin and the Synapse

Barron

Hurley

Parsons

2021

Front. Cell. Neurosci.

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“…Although we cannot fully exclude the possibility that signal propagation is also shaped by secreted inhibitors at later stages of these signaling events, the SMAD2/3 branch-specific effect could potentially be tied to differences in the targeting or localization of TGFβ, activin and BMP receptors. HTT plays an important role in endocytosis and its mutation affects endosomal recycling (McAdam et al, 2020;Moreira Sousa et al, 2013;Li et al, 2009). It has been shown that this can occur in a RAB11-dependent manner (Li et al, 2009), a mechanism that has been also implicated in the recycling of TGFβ receptors (Mitchell et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects

et al. 2021

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Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG repeats in the huntingtin gene (HTT). Although HD has been shown to have a developmental component, how early during human embryogenesis the HTT-CAG expansion can cause embryonic defects remains unknown. Here, we demonstrate a specific and highly reproducible CAG length-dependent phenotypic signature in a synthetic model for human gastrulation derived from human embryonic stem cells (hESCs). Specifically, we observed a reduction in the extension of the ectodermal compartment that is associated with enhanced activin signaling. Surprisingly, rather than a cell-autonomous effect, tracking the dynamics of TGFβ signaling demonstrated that HTT-CAG expansion perturbs the spatial restriction of activin response. This is due to defects in the apicobasal polarization in the context of the polarized epithelium of the 2D gastruloid, leading to ectopic subcellular localization of TGFβ receptors. This work refines the earliest developmental window for the prodromal phase of HD to the first 2 weeks of human development, as modeled by our 2D gastruloids.

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“…The SMAD2/3 branch specific effect could potentially be tied to differences in the targeting or localization of TGFβ, ACTIVIN and BMP receptors. HTT plays an important role in endocytosis and its mutation affects endosomal recycling 36-38 . It has been shown that this can occur through a Rab-11-dependent manner 38 , a mechanism that has been also implicated in the recycling of TGFβ receptors 39 .…”

Section: Discussionmentioning

confidence: 99%

Huntingtin CAG expansion impairs germ layer patterning in synthetic human gastruloids through polarity defects

Galgoczi

Ruzo

Markopoulos

et al. 2021

Preprint

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Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG repeats in the Huntingtin gene (HTT). While HD has been shown to have a developmental component, how early during human embryogenesis the HTT-CAG expansion can cause embryonic defects remains unknown. Here, we demonstrate a specific and highly reproducible CAG length-dependent phenotypic signature in a synthetic model for human gastrulation derived from human embryonic stem cells (hESCs). Specifically, we observed a reduction in the extension of the ectodermal compartment that is associated with enhanced ACTIVIN signaling. Surprisingly, rather than a cell-autonomous effect, tracking the dynamics of TGFb signaling demonstrated that HTT-CAG expansion perturbs the spatial restriction of ACTIVIN response. This is due to defects in the apicobasal polarization in the context of the polarized epithelium of the gastruloid, leading to ectopic subcellular localization of TGFb receptors. This work refines the earliest developmental window for the prodromal phase of HD to the first two weeks of human development as modeled by our gastruloids.

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Loss of huntingtin function slows synaptic vesicle endocytosis in striatal neurons from the httQ140/Q140 mouse model of Huntington's disease

Cited by 26 publications

References 61 publications

Huntingtin and the Synapse

Huntingtin and the Synapse

Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects

Huntingtin CAG expansion impairs germ layer patterning in synthetic human gastruloids through polarity defects

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