Huntingtin and the Synapse - PubMed (original) (raw)

Review

Huntingtin and the Synapse

Jessica C Barron et al. Front Cell Neurosci. 2021.

Abstract

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.

Keywords: Huntingtin; Huntington disease; autophagy; endocytosis; excitotoxicity; exocytosis; intracellular tranport; synaptic plastcity.

Copyright © 2021 Barron, Hurley and Parsons.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1

FIGURE 1

Huntingtin and the presynapse. (A) Select examples demonstrating how wtHTT positively regulates endocytosis (left). Through associations with ADAM10 and piccolo, wtHTT regulates SV density at the readily releasable and reserve vesicle pools. Through associations with HIP1, AP-2 and ADAM10, wtHTT regulates clathrin-mediated endocytosis. wtHTT loss impairs endocytosis by disrupting the function of complexes with the aforementioned proteins (right). wtHTT LOF decreases SV density at the readily releasable and reserve vesicle pools and impairs clathrin-mediated endocytosis. (B) Select examples demonstrating how wtHTT positively regulates exocytosis. Through its associations with synapsin-1, HAP1 and HIP1, wtHTT can regulate the rate of SV exocytosis and the amount of neurotransmitter release. wtHTT loss disrupts exocytosis (right). (C) Select examples demonstrating how wtHTT positively regulates axonal transport (top). Through its associations with HAP1 and HIP1, as well as molecular motors, wtHTT maintains proper anterograde and retrograde transport of cellular cargoes including SVs and DCVs. wtHTT loss impairs axonal transport (bottom). Due to its associations with HAP1 and HIP1, as well as molecular motors, wtHTT loss interferes with anterograde and retrograde transport of cellular cargoes including SVs and DCVs. Abbreviations: LOF, loss of function; ADAM10, A disintegrin and metalloproteinase domain-containing protein 10; HIP1, huntingtin-interacting protein 1; AP-2, adaptor protein complex 2; SV, synaptic vesicle; HAP1, huntingtin-associated protein 1; DCV, dense-core vesicle. Figure created using

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FIGURE 2

FIGURE 2

Huntingtin and the postsynapse. (A) Select examples demonstrating how wtHTT positively regulates dendritic transport (top). Through its associations with HAP1, as well as molecular motors, wtHTT regulates anterograde and retrograde transport of synaptic receptors and other cargo in dendrites (left). wtHTT LOF disrupts this transport and slows delivery of synaptic cargo to their respective anterograde or retrograde targets (bottom). (B) Select examples demonstrating how wtHTT positively regulates receptor localization (left). Through its associations with HIP14 and PSD-95, wtHTT regulates synaptic receptor stabilization at the PSD in a healthy postsynaptic neuron. wtHTT LOF disrupts postsynaptic protein clustering and receptor localization (right). Abbreviations: LOF, loss of function; HAP1, huntingtin-associated protein 1; SV, synaptic vesicle; NF-κB, nuclear factor kappa B; AMPAR, α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDAR, N-Methyl-D-aspartate receptor; HIP14/HIP14L, huntingtin-interacting protein 14/huntingtin-interacting protein 14-like; PSD-95, postsynaptic density protein 95. Figure created using

Biorender.com

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