Polyamine pathway contributes to the pathogenesis of Parkinson disease.

The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.

Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation.

Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.

Low Serum Levels of Fibroblast Growth Factor 2 in Gunn Rats: A Hyperbilirubinemia Animal Model of Schizophrenic Symptoms.

BACKGROUND: Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and prodifferentiation of neurons. METHOD: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. RESULTS: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied. CONCLUSION: Since it is known that FGF2 regulates dopaminergic neurons and have antineuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles.

Parvalbumin-positive GABAergic interneurons deficit in the hippocampus in Gunn rats: A possible hyperbilirubinemia-induced animal model of schizophrenia.

A reduction of GABAergic markers in postmortem tissue is consistently found in schizophrenia. Importantly, these alterations in GABAergic neurons are not global, which means they are more prevalent among distinct subclasses of interneurons, including those that express the calcium binding protein parvalbumin. A decreased expression of parvalbumin in the hippocampus is a consistent observation not only in postmortem human schizophrenia patients, but also in a diverse number of rodent models of the disease. Meanwhile, previously we reported that the congenital hyperbilirubinemia model rats (Gunn rats), which is a mutant of the Wistar strain, showed behavioral abnormalities, for instance, hyperlocomotor activity, deficits of prepulse inhibition, inappropriate social interaction, impaired recognition memory similar with several rodent models of schizophrenia. Several animal studies linked the importance of palvalbumin in relation to abnormal hippocampal activity and schizophrenia-like behavior. Here, we show that parvalbumin positive cell density was significantly lower in the CA1, CA3 and the total hippocampus of Gunn rats (congenital hyperbilirubinemia model rats) compared to Wistar control rats. The correlations between serum UCB levels and loss of PV expression in the hippocampus were also detected. The decreases in the PV-expression in the hippocampus might suggest an association of the behavioral abnormalities as schizophrenia-like behaviors of Gunn rats, compared to the Wistar control rats.