Abnormal association of mutant huntingtin with synaptic vesicles inhibits glutamate release

Abstract

In Huntington disease (HD), polyglutamine expansion causes the disease protein huntingtin to aggregate and accumulate in the nucleus and cytoplasm. The cytoplasmic huntingtin aggregates are found in axonal terminals and electrophysiological studies show that mutant huntingtin affects synaptic neurotransmission. However, the biochemical basis for huntingtin-mediated synaptic dysfunction is unclear. Using electron microscopy on sections of HD mouse brains, we found that axonal terminals containing huntingtin aggregates often had fewer synaptic vesicles than did normal axonal terminals. Subcellular fractionation and electron microscopy revealed that mutant huntingtin is co-localized with huntingtin-associated protein-1 (HAP1) in axonal terminals in the brains of HD transgenic mice. Mutant huntingtin binds more tightly to synaptic vesicles than does normal huntingtin, and it decreases the association of HAP1 with synaptic vesicles in HD mouse brains. Brain slices from HD transgenic mice that had axonal aggregates showed a significant decrease in [(3)H]glutamate release, suggesting that neurotransmitter release from synaptic vesicles was impaired. Taken together, these findings suggest that mutant huntingtin has an abnormal association with synaptic vesicles and this association impairs synaptic function.

Enhanced Sensitivity of Striatal Neurons to Axonal Transport Defects Induced by Mutant Huntingtin

“…Huntingtin associates with microtubules and various vesicles including mitochondria and synaptic vesicles (DiFiglia et al, 1995;Bhide et al, 1996;Velier et al, 1998;Li et al, 2003). Both huntingtin and the huntingtin-associated protein 1 (HAP1) move in axons in both anterograde and retrograde directions (Block-Galarza et al, 1997) and have been reported to associate with both the anterograde and retrograde transport machinery (Engelender et al, 1997;Li et al, 1998;McGuire et al, 2006;Caviston et al, 2007).…”

Inhibition of Calcineurin by FK506 Protects against Polyglutamine-Huntingtin Toxicity through an Increase of Huntingtin Phosphorylation at S421

“…In addition, when huntingtin contains the polyQ expansion, its ability to transport BDNF-containing vesicles and to promote neuronal survival is lost . Finally, aggregates are also found in neurites and could also participate in neuronal dysfunction by altering the microtubule network dynamics and/or axonal transport (Li et al, 2000(Li et al, , 2003Gunawardena et al, 2003;Szebenyi et al, 2003;Guzik and Goldstein, 2004;Lee et al, 2004;Trushina et al, 2004;Charrin et al, 2005). Several posttranslational modifications such as proteolysis, ubiquitination, and sumoylation modify the toxicity of huntingtin (Kalchman et ).…”

Huntington's disease and steroid hormone receptors

“…Li demonstrated that mutant htt may interact with synaptic vesicle membrane proteins or proteins associated with vesicles in axonal terminals. One of these interacting proteins may be Huntingtin-associated protein1 (HAP1) 3,11,20 . Steroid hormone receptors are a special type of receptors because of their localisation in the cytoplasm or nucleus of eukaryotic cells.…”

“…The fact that HD presents with a varied clinical picture prompted us to study the pathways and functions of steroid hormone receptors in vitro and mainly on HD model in animal. As we know, HD mouse model was compiled and as stipulated by Li 11 , we know that studies comprising HD mouse models provide compelling evidence to the fact that the N-terminal fragments of mutant Huntingtin protein(htt) with expanded glutamine repeat (82Q or 150Q) "cause neurological symptoms resembling some of the clinical features of HD" 2,11,14 . By constructing plasmid pEGFP-C2-ERα and others we would like to utilise the potential cooperation of SHR on HD for the purposes of highlighting the potential and prospective methods of assisting in remedying the behavioural, cognitive and memory defi ciencies found in HD.…”

“…Among the pathophysiological and degenerative changes of somewhat moderate intensity, the striate spiny neurons have been implicated; such cells are known to induce GABAdescribed degenerative changes in the neocortex. The signifi cance and function of normal as well as mutagenous Huntingtin protein (htt) is currently the subject of intensive study 11,15,18 . Our study aims to focus on determining the role of a group of steroid receptors, mainly the estrogen hormone receptors (ER), in Huntington's Disease.…”