Lower number of cerebellar Purkinje neurons in psychosis is associated with reduced reelin expression.

Reelin is an extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function. In the cerebellum of schizophrenia (SZ) and bipolar (BP) disorder patients, there is a marked decrease ( approximately 50%) of reelin expression. In this study we measured Purkinje neuron density in the Purkinje cell layer of cerebella of 13 SZ and 17 BP disorder patients from the McLean 66 Cohort Collection, Harvard Brain Tissue Resource Center. The mean number of Purkinje neurons (linear density, neurons per millimeter) was 20% lower in SZ and BP disorder patients compared with nonpsychiatric subjects (NPS; n = 24). This decrease of Purkinje neuron linear density was unrelated to postmortem interval, pH, drugs of abuse, or to the presence, dose, or duration of antipsychotic medications. A comparative study in the cerebella of heterozygous reeler mice (HRM), in which reelin expression is down-regulated by approximately 50%, showed a significant loss in the number of Purkinje cells in HRM (10-15%) compared with age-matched (3-9 months) wild-type mice. This finding suggests that lack of reelin impairs GABAergic Purkinje neuron expression and/or positioning during cerebellar development.

The Decrease of n-3 Fatty Acid Energy Percentage in an Equicaloric Diet Fed to B6C3Fe Mice for Three Generations Elicits Obesity.

Feeding mice, over 3 generations, an equicaloric diet in which alpha-linolenic acid, the dietary precursor of n-3 polyunsaturated fatty acids, was substituted by linoleic acid, the dietary precursor of n-6 polyunsaturated fatty acids, significantly increased body weight throughout life when compared with standard diet-fed mice. Adipogenesis observed in the low n-3 fatty acid mice was accompanied by a 6-fold upregulation of stearyl-coenzyme A desaturase 1 (Scd1), whose activity is correlated to plasma triglyceride levels. In total liver lipid and phospholipid extracts, the sum of n-3 fatty acids and the individual longer carbon chain acids, eicosapentaenoic acid (20:5n3), docosapentaenoic acid (22:5n3), and docosahexaenoic acid (22:6n3) were significantly decreased whereas arachidonic acid (20:4n6) was significantly increased. In addition, low n-3 fatty acid-fed mice had liver steatosis, heart, and kidney hypertrophy. Hence, reducing dietary alpha-linolenic acid, from 1.02 energy % to 0.16 energy % combined with raising linoleic acid intake resulted in obesity and had detrimental consequences on organ function.

The yeast cytosolic thioredoxins are involved in the regulation of methionine sulfoxide reductase A.

Previously we have shown that the binding complex formation of methionine sulfoxide reductase A (msrA) promoter and calcium phospholipid binding protein (CPBP) enhances msrA transcription and expression. The msrA promoter-CPBP-binding complex (PmsrA-CPBP) formation was similar in Deltatrx1, Deltatrx2, and Deltatrx3 yeast strains and their control, with or without exposure to H(2)O(2). In Deltatrx1/Deltatrx2 double mutant the PmsrA-CPBP was similar to its parent strain, following exposure to H(2)O(2) for 30 min. However, a late-onset loss of PmsrA-CPBP binding activity occurred following exposure to H(2)O(2) for 24 hours. Hence, it was inferred that both Trx1 and Trx2 are involved in the PmsrA-CPBP formation during prolonged oxidative stress conditions. In addition, the survival rate of the Deltatrx1Delta/trx2 double mutant was approximately 10% of its parent strain when exposed to H(2)O(2.) The MsrA activity was obliterated in Deltatrx1/Deltatrx2 and Deltatrx1 strains and remained intact in the Deltatrx2 and Deltatrx3 strains. The msrA mRNA level in Deltatrx1 was significantly reduced in comparison to that of its control, slightly reduced in Deltatrx2, and unchanged in Deltatrx3, respectively. It is suggested that under normal growth conditions Trx1 is essential for msrA transcription and activity. Moreover, following long-term oxidative stress conditions, Trx1 and Trx2 appear to promote PmsrA-CPBP-binding activity and cell survival.

A homologue of elongation factor 1 gamma regulates methionine sulfoxide reductase A gene expression in Saccharomyces cerevisiae.

Methionine sulfoxide reductase A (MsrA) maintains the function of many proteins by reversing oxidation of methionine residues. Lack of this repair mechanism very likely increases aging-related disease susceptibility. In Saccharomyces cerevisiae, disruption of the msrA gene increases free and protein-bound methionine sulfoxide and decreases cell viability. Although the underlying mechanisms in the induction of the msrA gene are still unknown, a transcriptional regulation may be involved. Hence, a search of nuclear proteins regulating the msrA gene is a major target of the experiments reported in this article. Using protein purification combined with MS, we discovered that calcium phospholipid-binding protein (CPBP), a homologue of elongation factor-1 gamma, is a component of a complex that binds to the msrA promoter. By measuring CPBP cooperative binding to the msrA promoter, we have mapped the CPBP binding site to a 39-bp sequence at the 3' end of the promoter. In a mutant yeast strain lacking the CPBP-encoding gene, the ability to overexpress msrA mRNA and MsrA protein was impaired and MsrA catalytic activity was greatly reduced, suggesting that CPBP may enhance msrA gene expression.