Learn More
N-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas(More)
Predictive genetic testing for Huntington's disease (HD) has revealed early cognitive deficits in asymptomatic gene carriers, such as altered working memory, executive function and impaired recognition memory. The perirhinal cortex processes aspects of recognition memory and the underlying mechanism is believed to be long-term depression (LTD) of excitatory(More)
BACKGROUND The introduction of gene testing for Huntington's disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working(More)
Huntington's disease (HD) is a progressive, fatal neurological condition caused by an expansion of CAG (glutamine) repeats in the coding region of the Huntington gene. To date, there is no cure but great strides have been made to understand pathophysiological mechanisms. In particular, genetic animal models of HD have been instrumental in elucidating the(More)
The NMDAR plays a unique and vital role in subcellular signaling. Calcium influx initiates signaling cascades important for both synaptic plasticity and survival; however, overactivation of the receptor leads to toxicity and cell death. This dichotomy is partially explained by the subcellular location of the receptor. NMDARs located at the synapse stimulate(More)
Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor, psychiatric and cognitive decline. Marked neuronal loss occurs in the cortex and striatum. HD is inherited in an autosomal dominant fashion and caused by a trinucleotide repeat expansion (CAG) in the gene encoding the protein huntingtin. Predictive genetic(More)
In Huntington's disease (HD), the mutant huntingtin (mhtt) protein is associated with striatal dysfunction and degeneration. Excitotoxicity and early synaptic defects are attributed, in part, to altered NMDA receptor (NMDAR) trafficking and function. Deleterious extrasynaptic NMDAR localization and signalling are increased early in yeast artificial(More)
Investigations of synaptic transmission and plasticity in mouse models of Huntington's disease (HD) demonstrate neuronal dysfunction long before the onset of classical disease indicators. Similarly, recent human studies reveal synaptic dysfunction decades before predicted clinical diagnosis in HD gene carriers. These studies guide premanifest tracking of(More)
Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that(More)
Mutations in Leucine-Rich Repeat Kinase-2 (LRRK2) result in familial Parkinson's disease and the G2019S mutation alone accounts for up to 30% in some ethnicities. Despite this, the function of LRRK2 is largely undetermined although evidence suggests roles in phosphorylation, protein interactions, autophagy and endocytosis. Emerging reports link loss of(More)