Huntingtin and the Synapse

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