Rolando Meloni

Association of DNA polymorphism in the first intron of the tyrosine hydroxylase gene with disturbances of the catecholaminergic system in schizophrenia

We examined whether there are clinical or biological differences in chronic schizophrenic patients sharing a rare variant allele (a perfect ten tetranucleotide repeats allele of the human TH01 microsatellite) in the tyrosine hydroxylase (TH) gene. For that purpose, clinical parameters (PANSS subscores) and plasma measurements (homovanillic acid and 3-methoxy-4-hydroxy-phenylglycol (MHPG)) were analyzed in five schizophrenic patients sharing the rare allele and 19 schizophrenic patients who did not possess this allele. The mean concentration of plasma HVA and plasma MHPG were significantly lower in the group of schizophrenic patients sharing the rare allele. No other group differences were observed between both groups. These results suggest that this TH gene polymorphism may be associated with disturbances of the catecholaminergic pathway.

Catecholamine metabolism and psychiatric or behavioral disorders

A wealth of pharmacological data point to the involvement of catecholamine metabolism in a number of psychiatric and behavioral disorders. Furthermore, evidence points to many of these affective disorders having a moderate to large genetic component. These observations have provided the impetus to search for differences between individuals in the structure and regulatory elements of genes involved in catecholaminergic neurotransmission. The recent finding that a mutation in the structural gene for the enzyme monoamine oxidase A is associated, in several males of a large kindred, with borderline mental retardation and abnormal behavior is an important breakthrough in the field. Other promising results concern the tyrosine hydroxylase gene in manic depressive illness and the dopamine D2 receptor in alcoholism. These studies, their potential significance and difficulties in dealing with such complex disorders are discussed.

Post-genomic era and gene discovery for psychiatric diseases: There is a new art of the trade?

The microsatellite HUMTH01, located in the first intron of the Tyrosine Hydroxylase (TH) gene (encoding the rate-limiting enzyme in the synthesis of catecholamines), is characterized by a TCAT repeated motif and has been used in genetic studies of neuropsychiatric and other complex diseases, in which catecholaminergic neurotransmission is implicated. After reporting a positive association between HUMTH01 and bipolar disorder as well as schizophrenia, the authors established that HUMTH01 alleles display the features of regulatory elements. Thereafter, they cloned two proteins (ZNF191 and HBP1), specifically binding to HUMTH01, and demonstrated that allelic variations of HUMTH01 have a quantitative silencing effect on TH gene expression in vitro, and correlate with quantitative and qualitative changes in the binding by ZNF191. The authors aim to characterize the transduction pathway impinging on the HUMTH01 microsatellite and establish its relevance for TH gene regulation in vivo. Since the TCAT repeated sequence is widespread throughout the genome, their approach may lead to the dissection of the mechanisms underlying the quantitative expression of several genes implicated in complex genetic traits, both normal and pathological. Thus, these investigations on the possible contribution and potential role of the HUMTH01 microsatellite in neuro-pathological conditions may represent an example of the different approaches needed to validate genetic targets in the “post-genomic era.”

The Extract of Ginkgo biloba EGb 761 Reactivates a Juvenile Profile in the Skeletal Muscle of Sarcopenic Rats by Transcriptional Reprogramming

Background Sarcopenia is a major public health problem in industrialized nations, placing an increasing burden on public healthcare systems because the loss of skeletal muscle mass and strength that characterizes this affection increases the dependence and the risk of injury caused by sudden falls in elderly people. Albeit exercise and caloric restriction improve sarcopenia-associated decline of the muscular performances, a more suitable and focused pharmacological treatment is still lacking. Methodology/Principal Findings In order to evaluate such a possible treatment, we investigated the effects of EGb 761, a Ginkgo biloba extract used in chronic age-dependent neurological disorders, on the function of the soleus muscle in aged rats. EGb 761 induced a gain in muscular mass that was associated with an improvement of the muscular performances as assessed by biochemical and electrophysiological tests. DNA microarray analysis shows that these modifications are accompanied by the transcriptional reprogramming of genes related to myogenesis through the TGFβ signaling pathway and to energy production via fatty acids and glucose oxidation. EGb 761 restored a more juvenile gene expression pattern by regenerating the aged muscle and reversing the age-related metabolic shift from lipids to glucose utilization. Conclusions/Significance Thus, EGb 761 may represent a novel treatment for sarcopenia both more manageable and less cumbersome than exercise and caloric restriction.

Catecholamine Biosynthetic Enzyme Expression in Neurological and Psychiatric Disorders

Publisher Summary The TH gene has been implicated in the genetics of one neurological disease, hereditary progressive dystonia (HPD), an l -dopa responsive form of dystonia in childhood. A transition C>T in the highly conserved exon 11 of TH has been shown to be responsible for HPD. The crucial rate-limiting role played by tyrosine hydroxylase (TH) in the catecholamine biosynthetic pathway could a priori implicate it in neurological or psychiatric diseases. Several studies have, moreover, implicated TH in psychiatric diseases. In the laboratory the role of the TH gene in bipolar disorders (BPD) and schizophrenia (SZ) has been investigated, using molecular genetics techniques. Family, twin, and adoption studies provide evidence that BPD and SZ have a strong genetic component. However, these diseases do not show a classical mendelian mode of inheritance, suggesting that the phenotype is determined by an unknown number of genes (polygenicity) that may vary (heterogeneity) with variable penetrance and the intervention of environmental factors. Nonparametric approach shows that the TH gene is associated both with BPD and SZ. The T10p allele, in spite of having a higher frequency in this second SZ population, did not attain statistical significance compared with the control population, most probably because of the relatively small size of the sample used. Thus, the perfect repeat was rare and found only in the SZ patients, in both the French and the Tunisian populations. The results obtained show that a composite approach using molecular biology and molecular genetics techniques is fruitful in establishing an eventual role for the TH gene in neurological and psychiatric diseases.