Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synucleins are small proteins regulating the filamentous network that in turn influences the release of dopamine and glutamate neurotransmitters involved in mood and motivation processes. We have studied the pattern of synuclein expression in animal models for mania and depression. Dominant behavior, as defined in a food competition test with dyads of rats, can serve as a model of mania and submissive behavior as a model of depression. The expression of alpha-, beta- and gamma-synuclein was analyzed in four regions of cortex from dominant, neutral and submissive rats using TaqMan reverse transcription-polymerase chain reaction technology. The expression levels of gamma-synuclein were elevated consistently in all regions of cerebral cortex of dominant rats (P <0.05; 23.5 +/- 1.1, normalized units) in contrast to the submissive rat group (10.3 +/- 1.2). Neutral rats had intermediate cerebral cortex levels of gamma-synuclein expression (15.7 +/- 1.4) that were significantly lower than that in dominant rats (P <0.05). No changes in alpha- or beta-synuclein expression were observed among the groups. These studies indicate that gamma-synuclein levels in the cerebral cortex were differentially associated with dominant and submissive behavior.
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PMID:Different levels of gamma-synuclein mRNA in the cerebral cortex of dominant, neutral and submissive rats selected in the competition test. 1566 Jun 69

The mechanisms underlying depression remain elusive. We previously determined that alpha-synuclein (alpha-Syn) modulates the activity and trafficking of the norepinephrine transporter (NET) in a manner that is dependent on its interactions with microtubules (MTs). Here we sought to determine if alpha-Syn, or the other synuclein family members, beta-synuclein (beta-Syn) and gamma-synuclein (gamma-Syn), modulate NET activity in an animal model of depression, the Wistar-Kyoto (WKY) rat. The NET-selective antidepressant desipramine (DMI) was chronically administered for 14 days to WKY rats and the strain from which it was outbred that does not show depressive-like behavior, the Wistar rat. This drug regimen induced significant behavioral improvements in the WKY, but not the Wistar rat, in the forced swim test. In WKY rats there was an overexpression of gamma-Syn which was reduced following DMI treatment. In parallel, DMI caused an increase in both alpha-Syn and NET in the frontal cortex. Frontal cortex synaptosomes from WKY rats were not sensitive to nocodazole, a compound that promotes MT destabilization. However, in WKYs treated with DMI, nocodazole induced an increase in [(3)H]-NE uptake. This trend was reversed in Wistars. Underlying these DMI-induced changes were alterations in the protein interactions between the synucleins and NET with the tubulins. These results are the first to implicate alpha-Syn or gamma-Syn in the pathophysiology of depression and suggest that targeting synucleins may provide a new therapeutic option for depression.
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PMID:Desipramine modulation of alpha-, gamma-synuclein, and the norepinephrine transporter in an animal model of depression. 1880 64

The role of alpha-synuclein (alphaSyn) in schizophrenia is unknown, whereas in a recent animal model of depression, alpha- and gamma-synuclein have been related to its pathophysiology. Previous biochemical studies in Brodmann area 9 showed significant reduction of alphaSyn in both chronic schizophrenia and bipolar disorder. Here, prevalence and cerebral distribution of alphaSyn were examined in 80 autopsy cases of elderly subjects (41 chronic schizophrenia, 12 late live depression/LLD and bipolar disorder/BD, and 27 age-matched controls without neuropsychiatric disorders). Using immunohistochemistry, alphaSyn-positive lesions (Lewy bodies and neurites) were assessed semiquantitatively. Among 41 chronic schizophrenics, all except one showing low neuritic Braak stages (mean 1.46), three brains (7.3%) revealed only few alphaSyn-positive inclusions restricted to medullary nuclei. Among 12 LLD and BD patients with mean Braak stage 2.25, alphaSyn-positive pathology was seen in two cases (16.7%) with clinical LLD, but none in BD. Among 27 controls, showing mean neuritic Braak stage 2.6, seven brains (26%) with higher mean age showed alphaSyn-positive lesions, either isolated in substantia nigra and nucleus basalis of Meynert (n = 2 each), in medullary nuclei, locus ceruleus and substantia nigra (n = 2), with additional involvement of nucleus basalis (n = 1). This first preliminary study in non-demented psychiatric disorders indicates that alphaSyn/Lewy pathology in chronic schizophrenia is significantly less frequent than in clinically healthy elderly people (P < 0.01), showing 10-30% of so-called incidental Lewy body disease. Among chronic affective disorders, according to our small cohort, the incidence of Lewy-pathology in LLD appears to be comparable to a healthy elderly population, whereas its occurence in BD is to be elucidated.
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PMID:Lewy body/alpha-synucleinopathy in schizophrenia and depression: a preliminary neuropathological study. 1919 57

Human alpha-synuclein (alpha-Syn) is instrumental in maintaining homeostasis of monoamine neurotransmitters in brain, through its trafficking, and regulation of the cell surface expression and, thereby, activity of dopamine, serotonin and norepinephrine transporters. Here we have investigated whether other members of the synuclein family of proteins, gamma-synuclein (gamma-Syn) and beta-synuclein (beta-Syn) can similarly modulate the serotonin transporter (SERT). In Ltk(-) cells co-transfected with SERT and gamma-Syn, gamma-Syn reduced [(3)H]5-HT uptake, in a manner dependent on its expression levels. The decrease in SERT activity was via decreased V(max) of the transporter, without change in K(m), compared to cells expressing only SERT. By contrast, beta-Syn co-expression failed to alter SERT uptake activity, and neither the V(max) nor the K(m) was changed in the presence of beta-Syn. gamma-Syn modulation of SERT was only partial, with a maximal approximately 27% decrease in SERT activity seen even at high expression levels of gamma-Syn. By contrast, alpha-Syn attenuated SERT activity by approximately 65% at identical expression levels as gamma-Syn. Co-immunoprecipitation studies showed the presence of heteromeric protein:protein complexes between gamma-Syn or alpha-Syn and SERT, while beta-Syn failed to physically interact with SERT. Both alpha-Syn and gamma-Syn colocalized with SERT in rat primary raphae nuclei neurons. These studies document a novel physiological role for gamma-Syn in regulating 5-HT synaptic availability and homeostasis, and may be of relevance in depression and mood disorders, where SERT function is dysregulated.
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PMID:Partial regulation of serotonin transporter function by gamma-synuclein. 1942 25

The high incidence of depression in Parkinson's disease (PD) has been well documented in the clinic; however, the underlying molecular mechanisms of these overlapping pathologies remain elusive. Using a rodent model of depression, the Wistar-Kyoto (WKY) rat, we previously demonstrated that in the frontal cortex the altered expression and protein interactions of alpha- and gamma-synuclein (alpha-Syn, gamma-Syn) were associated with dysregulated trafficking of the norepinephrine transporter (NET). Chronic treatment with desipramine (DMI), a NET-selective antidepressant, caused a disappearance of depressive-like behavior that was accompanied by a change in alpha-Syn and gamma-Syn expression and their trafficking of NET. Using this same model, we examined the expression of NET, alpha-Syn and gamma-Syn in the hippocampus, amygdale, brainstem, and striatum, all regions implicated in the development or maintenance of depression or PD pathology. Following chronic treatment with DMI, we observed a significant decrease in NET in the hippocampus, amygdala, and brainstem; decrease in gamma-Syn in the hippocampus and amygdala; and, increase in alpha-Syn in the hippocampus and amygdala. Unexpectedly, we observed a significant decrease in alpha-Syn expression in the striatum of the WKY following chronic DMI treatment. The altered expression of NET, alpha-Syn and gamma-Syn in different brain suggest that DMI's ability to improve depressive-like behavior in a rodent is associated with region-specific changes in the regulation of NET by alpha- and gamma-Syn.
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PMID:Desipramine induced changes in the norepinephrine transporter, alpha- and gamma-synuclein in the hippocampus, amygdala and striatum. 1981 34