Mutant huntingtin affects endocytosis in striatal cells by altering the binding of AP-2 to membranes

Borgonovo, Janina; Troncoso, Mariana; Lucas, José J.; Sosa, Miguel A. Gama

doi:10.1016/j.expneurol.2012.11.025

Cited by 17 publications

(9 citation statements)

References 47 publications

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“…NRF2, aldosterone, and retinoic acid receptor signaling pathway findings highlight the transcriptional role of HTT and its dysregulation in HD (36). The clathrin-mediated endocytosis pathway is known to be affected by mutant HTT (37,38). Our data from primary and secondary interacting partners indicate that multiple components of these pathways interact with mutant HTT.…”

Section: Network Properties Of Huntingtin-interacting Proteins Inmentioning

confidence: 75%

A Large Scale Huntingtin Protein Interaction Network Implicates Rho GTPase Signaling Pathways in Huntington Disease

Tourette

Bell

et al. 2014

Journal of Biological Chemistry

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Background: Huntington disease is a fatal neuropsychiatric disorder caused by aberrant protein folding and interactions. Results: An interaction network composed of primary and secondary huntingtin-interacting proteins is significantly enriched for pathways implicated in HD, including RhoGTPases. Conclusion: Huntingtin interacts with members of the Rho GTPase signaling pathways and regulates filipodial dynamics. Significance: This protein interaction network provides a resource for HD target discovery.

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Section: Network Properties Of Huntingtin-interacting Proteins Inmentioning

confidence: 75%

A Large Scale Huntingtin Protein Interaction Network Implicates Rho GTPase Signaling Pathways in Huntington Disease

Tourette

Bell

et al. 2014

Journal of Biological Chemistry

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“…Entry of oligomeric and amyloid assemblies of mHTT into a cell’s cytoplasmic compartment from the extracellular space or from a different cell cytoplasm has been reported to occur via multiple endocytic pathways ( Figure 3D ). polyQ expansion and protein aggregation can alter the interaction of HTT with endocytic machinery components and lead to endocytic dysfunction ( Parker et al, 2007 ; Davranche et al, 2011 ; Borgonovo et al, 2013 ). Genetic or pharmacological inhibition of receptor-mediated endocytosis, macropinocytosis, or the GTPase activity of dynamin reduces the ability of purified polyQ or mHTT ex1 fibrils to be internalized by multiple cultured mammalian cell types ( Holmes et al, 2013 ; Ruiz-Arlandis et al, 2016 ), suggesting that mHTT can enter cells from the extracellular space via multiple endocytic routes.…”

Section: Mechanisms Underlying Cell-to-cell Transmission Of Mutant Hu...mentioning

confidence: 99%

Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

et al. 2022

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The hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell-to-cell in the brain in a manner akin to infectious prions has gained substantial momentum due to an explosion of research in the past 10–15 years. Here, we review current evidence supporting the existence of prion-like mechanisms in Huntington’s disease (HD), an autosomal dominant neurodegenerative disease caused by expansion of a CAG repeat tract in exon 1 of the huntingtin (HTT) gene. We summarize information gained from human studies and in vivo and in vitro models of HD that strongly support prion-like features of the mutant HTT (mHTT) protein, including potential involvement of molecular features of mHTT seeds, synaptic structures and connectivity, endocytic and exocytic mechanisms, tunneling nanotubes, and nonneuronal cells in mHTT propagation in the brain. We discuss mechanisms by which mHTT aggregate spreading and neurotoxicity could be causally linked and the potential benefits of targeting prion-like mechanisms in the search for new disease-modifying therapies for HD and other fatal neurodegenerative diseases.

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“…Thus, wtHTT loss may have detrimental effects on presynaptic homeostasis by interrupting the HTT/ADAM10/piccolo complex. In addition to complexing with ADAM10/piccolo and other presynaptic regulatory proteins including bassoon ( Yao et al, 2014 ), wtHTT and ADAM10 both interact with the clathrin adaptor protein AP-2 ( Borgonovo et al, 2013 ; Marcello et al, 2013 ), and wtHTT serves as a docking protein that helps recruit AP-2 to the membrane. Interestingly, polyQ expansion of HTT results in a loss of wtHTT’s docking function, thereby reducing AP-2 presence at the membrane and impairing clathrin-mediated endocytosis ( Borgonovo et al, 2013 ).…”

Section: Huntingtin and The Presynapsementioning

confidence: 99%

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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Mutant huntingtin affects endocytosis in striatal cells by altering the binding of AP-2 to membranes

Cited by 17 publications

References 47 publications

A Large Scale Huntingtin Protein Interaction Network Implicates Rho GTPase Signaling Pathways in Huntington Disease

A Large Scale Huntingtin Protein Interaction Network Implicates Rho GTPase Signaling Pathways in Huntington Disease

Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

Huntingtin and the Synapse

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