Knockdown of mortalin within the medial prefrontal cortex impairs normal sensorimotor gating.

The 70-kDa mitochondrial heat shock protein, mortalin, is a ubiquitously expressed, multifunctional protein that is capable of binding the neurotransmitter, dopamine, within the brain. Dopamine dysregulation has been implicated in many of the abnormal neurological behaviors. Although studies have indicated that mortalin is differentially regulated in response to dopaminergic modulation, research has yet to elucidate the role of mortalin in the regulation of dopaminergic activity.

Antipsychotic drug use is correlated with CRP40/mortalin mRNA expression in the dorsolateral prefrontal cortex of human postmortem brain specimens.

Heat shock proteins act as intracellular chaperones by assisting with proper protein folding in response to various cellular stresses. In doing so, these proteins protect the cell from unwanted protein aggregation, which in turn, plays an important role in the pathogenesis of numerous disorders. Previous reports from our laboratory have described a 40 kDa catecholamine regulated heat shock-like protein (CRP40), an alternate gene product of the 70 kDa mitochondrial heat shock protein, mortalin.

Cloning, characterization, and functional studies of a human 40-kDa catecholamine-regulated protein: implications in central nervous system disorders.

Catecholamine-regulated proteins (CRPs) have been shown to bind dopamine and other structurally related catecholamines; in particular, the 40-kDa CRP (CRP40) protein has been previously cloned and functionally characterized. To determine putative human homologs, BLAST analysis using the bovine CRP40 sequence identified a human established sequence tag (EST) with significant homology (accession #BQ224193). Using this EST, we cloned a recombinant human brain CRP40-like protein, which possessed chaperone activity.

Co-operative roles for E-cadherin and N-cadherin during lens vesicle separation and lens epithelial cell survival.

The classical cadherins are known to have both adhesive and signaling functions. It has also been proposed that localized regulation of cadherin activity may be important in cell assortment during development. In the context of eye development, it has been suggested that cadherins are important for separation of the invaginated lens vesicle from the surface ectoderm.

Cell autonomous roles for AP-2alpha in lens vesicle separation and maintenance of the lens epithelial cell phenotype.

In this study, we have created a conditional deletion of AP-2alpha in the developing mouse lens (Le-AP-2alpha mutants) to determine the cell-autonomous requirement(s) for AP-2alpha in lens development. Embryonic and adult Le-AP-2alpha mutants exhibited defects confined to lens placode derivatives, including a persistent adhesion of the lens to the overlying corneal epithelium (or lens stalk). Expression of known regulators of lens vesicle separation, including Pax6, Pitx3, and Foxe3 was observed in the Le-AP-2alpha mutant lens demonstrating that these genes do not lie directly downstream of AP-2alpha.

Conditional deletion of activating protein 2alpha (AP-2alpha) in the developing retina demonstrates non-cell-autonomous roles for AP-2alpha in optic cup development.

Activating protein 2alpha (AP-2alpha) is known to be expressed in the retina, and AP-2alpha-null mice exhibit defects in the developing optic cup, including patterning of the neural retina (NR) and a replacement of the dorsal retinal pigmented epithelium (RPE) with NR. In this study, we analyzed the temporal and spatial retinal expression patterns of AP-2alpha and created a conditional deletion of AP-2alpha in the developing retina. AP-2alpha exhibited a distinct expression pattern in the developing inner nuclear layer of the retina, and colocalization studies indicated that AP-2alpha was exclusively expressed in postmitotic amacrine cell populations.

Targeted deletion of AP-2alpha leads to disruption in corneal epithelial cell integrity and defects in the corneal stroma.

Purpose: The present study was undertaken to create a conditional knockout of AP-2alpha in the corneal epithelium.

Methods: A line of mice expressing Cre-recombinase specifically in the early lens placode was crossed with mice in which the AP-2alpha allele is flanked by two loxP sites. The resultant Le-AP-2alpha mutants exhibited a targeted deletion of AP-2alpha in lens placode derivatives, including the differentiating corneal epithelium.

Decreased expression of a 40-kDa catecholamine-regulated protein in the ventral striatum of schizophrenic brain specimens from the Stanley Foundation Neuropathology Consortium.

The majority of heat shock proteins (HSP) act as molecular chaperones protecting cells from deleterious stress. These proteins are able to inhibit the aggregation of partially denatured proteins and refold them into the correct conformation. They have also been shown to be involved in the pathogenesis of many neurodegenerative and psychiatric disorders.

Iso-lactam and reduced amide analogues of the peptidomimetic dopamine receptor modulator 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide.

An analogue of the highly potent gamma-lactam Pro-Leu-Gly-NH(2) peptidomimetic, 3(R)-[(2(S)-pyrrolidinylcarbonyl) amino]-2-oxo-1-pyrrolidineacetamide (2), 4(R)-[[2(S)-pyrrolidinylcarbonyl]amino]-2-oxo-1-pyrrolidineacetamide (3), in which the lactam carbonyl moiety has been placed in a different position with respect to the 3-amino group was synthesized. Also, a series of analogues of 2, compounds 4-6, were synthesized in which each of the amide bonds of 2 were systematically replaced with a reduced amide bond surrogate. The analogues were tested for their ability to enhance the binding of [3H]N-propylnorapomorphine to dopamine receptors in a functional in vitro assay utilizing bovine striatal membranes.

Synthesis and dopamine receptor modulating activity of 3-substituted gamma-lactam peptidomimetics of L-prolyl-L-leucyl-glycinamide.

gamma-Lactam peptidomimetic 2 of Pro-Leu-Gly-NH(2) (PLG) was substituted at the 3-position with isobutyl, butyl, and benzyl moieties to give the PLG peptidomimetics 3-5, respectively. These compounds were synthesized to test the hypothesis that attaching a hydrophobic moiety to the lactam ring to mimic the isobutyl side chain of the leucyl residue of PLG would increase the dopamine receptor modulating activity of such peptidomimetics. These peptidomimetics were tested for their ability to enhance the binding of [(3)H]-N-propylnorapomorphine to dopamine receptors isolated from bovine striatal membranes.