Allelic series of Huntington's disease knock-in mice reveals expression discorrelates.

Identifying molecular drivers of pathology provides potential therapeutic targets. Differentiating between drivers and coincidental molecular alterations presents a major challenge. Variation unrelated to pathology further complicates transcriptomic, proteomic and metabolomic studies which measure large numbers of individual molecules.

Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice.

Chronic ethanol consumption increases sensitivity of the mitochondrial permeability transition (MPT) pore induction in liver. Ca(2+) promotes MPT pore opening, and genetic ablation of cyclophilin D (CypD) increases the Ca(2+) threshold for the MPT. We used wild-type (WT) and CypD-null (CypD(-/-)) mice fed a control or an ethanol-containing diet to investigate the role of the MPT in ethanol-mediated liver injury.

Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells.

Recent evidence suggests that interneurons are involved in the pathophysiology of Huntington Disease (HD). Abnormalities in the function of interneurons expressing the calcium buffer parvalbumin (PV) have been observed in multiple mouse models of HD, although it is not clear how PV-positive interneuron dysfunction contributes to behavioral and synaptic deficits. Here, we use the cre-lox system to drive expression of mutant huntingtin (mthtt) in parvalbumin (PV)-positive neurons and find that mutant mice exhibit diffuse mthtt immunoreactivity in PV-rich areas at 10months of age and mthtt aggregates in PV-positive processes at 24months of age.

Enhanced Ca(2+)-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model.

Huntington's disease (HD) causes preferential loss of a subset of neurons in the brain although the huntingtin protein is expressed broadly in various neural cell types, including astrocytes. Glutamate-mediated excitotoxicity is thought to cause selective neuronal injury, and brain astrocytes have a central role in regulating extracellular glutamate. To determine whether full-length mutant huntingtin expression causes a cell-autonomous phenotype and perturbs astrocyte gliotransmitter release, we studied cultured cortical astrocytes from BACHD mice.

Purkinje cell dysfunction and loss in a knock-in mouse model of Huntington disease.

Huntington Disease (HD) is an autosomal dominant neurological disorder characterized by motor, psychiatric and cognitive disturbances. Recent evidence indicates that the viability and function of cerebellar Purkinje cells (PCs) are compromised in an aggressive mouse model of HD. Here we investigate whether this is also the case in the HdhQ200 knock-in mouse model of HD.