Huntingtin and the Synapse

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.

Polyglutamine Expansion in Huntingtin and Mechanism of DNA Damage Repair Defects in Huntington’s Disease

“…There is ample evidence to suggest that subtle alterations of synapses occur before overt neuronal death, and that these changes are predictive of the onset of behavioral problems associated with HD ( Morton et al, 2001 ; Li H. et al, 2003 ; Joshi et al, 2009 ; Raymond et al, 2011 ). Huntingtin is highly expressed in the presynaptic terminals of nerve cells ( DiFiglia et al, 1995 ), and various proteins that regulate both the presynaptic and postsynaptic function have been shown to interact with HTT ( Li et al, 2002 ; Li J. Y. et al, 2003 ; Barron et al, 2021 ). These proteins affect a range of pre and postsynaptic functions, including endocytosis, synaptic homeostasis, and axonal transport on the presynaptic side, and postsynaptic receptor localization and dendritic protein transport at the post-synapse.…”

The evolutionary history of the polyQ tract in huntingtin sheds light on its functional pro-neural activities

“…Among these functions, HTT regulates neurogenesis and brain development, together with the survival and function of cortical and striatal neurons in the adult brain [ 8 , 9 ]. Molecularly, HTT scaffolds a large repertoire of binding proteins to coordinate several cellular processes, including gene transcription, synaptic activity, vesicles trafficking and autophagy [ 8 – 10 ]. In spite of this knowledge, the contribution of the non-pathogenic CAG tract itself and its highly polymorphic lengths in normal HTT function remains poorly examined.…”

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

“…This, however, stresses the need for further understanding of the function of normal HTT in cells. Several in vitro and in vivo studies showed that normal HTT is involved in numerous cellular processes, including cell maturation, vesicle trafficking, synaptic transmission, and neuroprotection (reviewed in [7][8][9][10]). Additionally, further knowledge about how gains-or losses-ofdysfunctional mHTT affects the various tissues and cell types throughout the body is needed.…”