Gene expression profiling in progressively MPTP-lesioned macaques reveals molecular pathways associated with sporadic Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of midbrain dopaminergic neurons. To gain an insight into the mechanisms underlying the progression of PD, gene expression analysis was performed using two different brain regions, the substantia nigra pars compacta (SN) and the striatum (STR), of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkey model of PD. 230 genes were differentially expressed in the MPTP-treated SN compared to control, whereas 452 genes showed altered expression in the MPTP-treated STR, implying that MPTP elicits more damages in the striatal gene expression than in the SN. Comparative data analysis of the transcription profiles on the PD patients and MPTP monkey models, and pathway analysis indicated several signaling pathways as possible routes to MPTP-induced neurodegeneration. Interestingly, the networks which associated with cytoskeletal stability, ubiquitin-proteasome system (UPS) and Wnt signaling gained prominence in our study. Further transcriptional regulatory network analysis suggested the association of the neuronal repressor REST (RE1-silencing transcription factor; NRSF) and androgen receptor with the dysregulation of the striatal genes. Our study suggests the possibility that the dysfunction of multi-network signaling may induce abnormalities in a diverse range of biological processes, such as synaptic function, cytoskeletal stability, survival and differentiation.

Transgenic mice over-expressing dicarbonyl/L-xylulose reductase gene crossed with KK-Ay diabetic model mice: an animal model for the metabolism of renal carbonyl compounds.

Carbonyl compounds in the blood stream tend to accumulate in the kidney of diabetic or end stage renal failure subjects. Previously we isolated cDNA encoding dicarbonyl/L-xylulose reductase (DCXR) from a mouse kidney cDNA library. In the present study, transgenic (Tg) mice were generated to study the functional role of DCXR in the kidney. With a six-fold increase in the DCXR protein expression levels in the kidney, the homozygous Tg mice did not show any notable histological abnormalities. While the elevated DCXR expression was observed throughout the body, its renal distribution was similar to that of the endogenous DCXR protein, namely, the major expression site was the collecting tubules, along with moderate expression in other tubules and Bowman's capsule, but it was absent from the interstitial area and glomeruli. The Tg mice were crossed with KK-A(y) diabetic model mice to examine the role of DCXR in the progression of diabetic nephropathy. The resulting progeny, Tg/A(y), showed lighter body weight, lower levels of blood glucose, water uptake and creatinine clearance compared to their +/A(y) littermates. Although remarkable pathological differences were not observed at the microscopic level and in the renal accumulation of carboxymethyl lysine, the data imply that DCXR might function in the metabolism of glucose or carbonyl compounds, and play a protective role in a kidney which is under hyperglycemic pressure. The DCXR Tg mice and the Tg x KK-A(y) hybrid mice, therefore, serve as specific models for carbonyl metabolism in the kidney with diabetic background.

Psychophysiological stress-regulated gene expression in mice.

Eight genes showed significant changes in expression in mice under psychophysiological stress provided by cage-restraint and water-immersion. The transcription level of most of these genes was affected in all the tissues analyzed, and some of them were responsive genes in several different stress systems. Peculiarly, the expression level of one gene, cdc2-like kinase 1 (CLK1), was reduced only in the brain, while the balance of partially- and alternatively-spliced CLK1 mRNA species changed in all the tissues including the brain. These results suggest that some stress-response mechanisms, including transcriptional and post-transcriptional events, are coordinated in the whole body in mice under psychophysiological stress.