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)

Although intracellular accumulation of alpha-synuclein (alpha-syn) is a characteristic pathological change in Parkinson's disease, Lewy body dementia and Alzheimer's disease, the normal function of this presynaptic protein is still unknown. To assess the contribution of alpha-syn to synaptic plasticity as well as to age-related synaptic degeneration in mice, we compared adult and aged mice overexpressing mutated (A30P) human alpha-syn with their nontransgenic littermates using behavioral tests and electrophysiological measures in the dentate gyrus. We found decreased basal synaptic transmission and paired-pulse facilitation in the perforant path-dentate granule cell synapses of aged mice. In addition, alpha-syn accumulation in aged A30P mice but not in aged wild-type mice led to long-term depression of synaptic transmission after a stimulation protocol that normally induces long-term potentiation. These findings suggest that overexpression of mutated alpha-syn exacerbates the aging process and leads to impaired synaptic plasticity.
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PMID:Aging and alpha-synuclein affect synaptic plasticity in the dentate gyrus. 1900 52

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

The proteinopathy sporadic Parkinson's disease (sPD) is the second most frequent degenerative disorder of the human nervous system after Alzheimer's disease. The alpha-synuclein inclusion body pathology (Lewy pathology) associated with sPD is distributed throughout the central, peripheral, and enteric nervous systems. The resulting nonrandom neuronal dysfunction and, in some regions, neuronal loss is reflected in a topographic distribution pattern of the Lewy pathology that, in the brain, can be staged. Except for olfactory structures and spinal cord constituents of the pain system, sensory components of the nervous system remain uninvolved or virtually intact. The most disease-related damage revolves around motor areas--particularly around superordinate centers of the limbic and visceromotor systems as well as portions of the somatomotor system. Vulnerable regions are interconnected anatomically and susceptible nerve cell types are not neurotransmitter-dependent. Not all clinical symptoms emerging in the course of sPD can be explained by a lack of dopamine in the nigrostriatal system. These include autonomic dysfunction, pain, hyposmia or anosmia, excessive daytime sleepiness, rapid eye movement (REM) sleep behavioral disorder, depression, anxiety, cognitive decline, and dementia. Against the background of the normal morphology and anatomy, the authors analyze the pathoanatomy of sPD in the nervous system at various neuropathological stages and summarize the potential functional consequences of the lesions.
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PMID:Neuroanatomy and pathology of sporadic Parkinson's disease. 1923 May 52

Most forms of Parkinson's disease (PD) are sporadic in nature, but some have genetic causes as first described for the alpha-synuclein gene. The alpha-synuclein protein also accumulates as insoluble aggregates in Lewy bodies in sporadic PD as well as in most inherited forms of PD. The focus of the present study is the modulation of synaptic plasticity in the corticostriatal pathway of transgenic (Tg) mice that overexpress the human alpha-synuclein protein throughout the brain (ASOTg). Paired-pulse facilitation was detected in vitro by activation of corticostriatal afferents in ASOTg mice, consistent with a presynaptic effect of elevated human alpha-synuclein. However basal synaptic transmission was unchanged in ASOTg, suggesting that human alpha-synuclein could impact paired-pulse facilitation via a presynaptic mechanism not directly related to the probability of neurotransmitter release. Mice lacking alpha-synuclein or those expressing normal and A53T human alpha-synuclein in tyrosine hydroxylase-containing neurons showed, instead, paired-pulse depression. High-frequency stimulation induced a presynaptic form of long-term depression solely in ASOTg striatum. A presynaptic, N-methyl-d-aspartate receptor-independent form of chemical long-term potentiation induced by forskolin (FSK) was enhanced in ASOTg striatum, while FSK-induced cAMP levels were reduced in ASOTg synaptoneurosome fractions. Overall the results suggest that elevated human alpha-synuclein alters presynaptic plasticity in the corticostriatal pathway, possibly reflecting a reduction in glutamate at corticostriatal synapses by modulation of adenylyl cyclase signaling pathways. ASOTg mice may recapitulate an early stage in PD during which overexpressed alpha-synuclein dampens corticostriatal synaptic transmission and reduces movement.
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PMID:Alterations in corticostriatal synaptic plasticity in mice overexpressing human alpha-synuclein. 1936 78

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

Dementia is becoming increasingly prevalent since elderly patients are living longer due to the development of treatments for other diseases and conditions. The percent of our population over 60 is also increasing with the wave of aging baby boomers. Additionally, more individuals seek medical assistance for cognitive problems as visibility for treatments improves. This combination of factors results in the dementia syndromes becoming more common, causing physicians to encounter more patients with dementia as well as more caregivers of these patients. Of dementia subtypes, Alzheimer's disease (AD) is the most common. Dementia with Lewy bodies (DLB) is thought to be the second most common subtype. DLB's typical symptoms include cognitive impairment, visual hallucinations, spontaneous parkinsonism, and fluctuating confusion. Supportive features include a variety of sleep disruptions that may occur before manifestations of dementia. Psychiatric symptoms include vivid visual hallucinations and depression. The clinical features of DLB are strikingly similar to those of dementia in Parkinson's disease (PD). The underlying biology of DLB is complex, but the presence of alpha-synuclein containing Lewy bodies (LB) is a common factor. These inclusions also contain ubiquitin. PD dementia shares these pathological findings with DLB, as well as neural degeneration of the substantia nigra. DLB and dementia in PD may represent the same pathological process along a disease spectrum. Additionally, many DLB cases are also associated with beta-amyloid and tau-containing neurofibrillary tangles, features that are associated with AD. Frequently, AD patients are also found to have LB. The reason for this overlap is unknown. However, the greater the Alzheimer's pathology in DLB patients, the more the clinical features of DLB overlaps with AD. In this chapter, we will review DLB including clinical, pathological, and radiological features as well as biomarkers and treatments.
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PMID:Lewy body dementia. 1950 20

Parkinson's disease is a common progressive bradykinetic disorder that can be accurately diagnosed. It is characterised by the presence of severe pars-compacta nigral-cell loss, and accumulation of aggregated alpha-synuclein in specific brain stem, spinal cord, and cortical regions. The main known risk factor is age. Susceptibility genes including alpha-synuclein, leucine rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another important causal factor. Dopamine replacement therapy considerably reduces motor handicap, and effective treatment of associated depression, pain, constipation, and nocturnal difficulties can improve quality of life. Embryonic stem cells and gene therapy are promising research therapeutic approaches.
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PMID:Parkinson's disease. 1952 82

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of nonmotor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA-responsive motor deficits, alpha-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine and serotonin), which are known to regulate some of these behaviors, the VMAT2-deficient mice may display some of the nonmotor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the nonmotor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the nonmotor symptoms of PD, and interventions aimed at restoring monoamine function may be beneficial in treating the disease.
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PMID:Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity. 1982 98

This study was aimed at evaluating the occurrence of DLB in a population sample recovered in assisted sanitary residence (RSA=from the Italian name of "Residenza Sanitaria Assistita") in the Province of Catania. We considered 126 patients from a randomized population recovered in RSA of Viagrande (Catania) in the period from 1st March, 2005 and 31st March, 2007. Those who proved to be demented according to the DSM-III diagnostic protocols, and having a mini mental state examination (MMSE)-score <24 were divided in 2 groups: Group A, all the demented people without the DLB; and Group B, the DLB patients, according to the diagnostic criteria of McKeith. All patients underwent at admission, after 1 month, and at emission the following psychometric and functional tests: MMSE, geriatric depression scale (GDS) [Yesavage J.A., Brink T.L., Rose T.L., Adey M., 1983. The development and validation of geriatric depression screening scale: a preliminary report. J. Psych. Res. 17, 37], Barthel index (BI), activities of daily living (ADL) and instrumental ADL (IADL). Particular attention was dedicated to the presence of delirium during the last 15 days before the admission and during the recovery, the mortality and the prevalence of other complaints. The observed data confirm the prevalence of fragility of DLB patients in 20% of them, a fluctuation of the cognitive capacities, a better recovery of the affectivity, a reduced functional autonomy and autosufficiency. In addition, the DLB patients display a major presence of prevalent delirium, compared to the total population of demented patients, while in this last population only incidental delirium episodes occurred during the recovery period (31.6% vs. 16.6%; p<0.001). In the DLB population decubital lesions occurred more frequently, and were of more severe staging, compared to the controls (45% vs. 27%; p<0.001). Also, the mortality of the DLB patients was higher (about 30% vs. 17% in 12 months). These data confirm the particularity and higher complexity of the DLB patients recovered in the RSA.
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PMID:The clinical and rehabilitative complexity in dementia with Lewy bodies (DLB): experience on a random sample of elderly patients dwelling in an RSA ("Residenza Sanitaria Assistita") of Catania. 1966 42

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are second only to Alzheimer's disease (AD) in frequency. In particular it is evident that up to 80% of people with PD will develop dementia towards the end of their life. While the neurobiology of movement disorder has been well studied in PD, much less attention has been given to mechanisms underlying the cognitive and behavioural symptoms associated with DLB and PDD. To date, the best correlate of cognitive impairment appears to be cortical Lewy bodies; however, new emphasis has been placed on small aggregates of synuclein. Furthermore, very few studies have attempted to investigate the neurochemical correlates of behavioural disorders in DLB/PDD and whether these are similar or distinct from AD. Aggregated alpha-synuclein forms the core component of Lewy bodies, a major pathological feature of Parkinson's-related conditions. The 26S proteasome is an ATP-dependent protease that catalyses the breakdown of alpha-synuclein. Previous studies have implicated alterations in the proteasome in PD. Furthermore, proteasome inhibitors have been reported to induce alpha-synuclein aggregation and Lewy body-like inclusions, resulting in neuronal loss both in vitro and in vivo. Our preliminary results indicate that selective alterations in the expression of proteosome sub-units are a feature of both DLB and PDD, while changes in activity are restricted to PDD. Depression is a common symptom in DLB/PDD, yet the evidence base for standard treatment with SSRIs is limited. In contrast to previous studies of AD, our results indicate that there is no association between depression and the 5-HT transporter, while there was a significant increase in the number of 5-HT1A receptors in those DLB/PDD patients with depression. These data may provide an insight into the lack of success of current treatments and suggest alternative approaches.
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PMID:Biochemical and pathological correlates of cognitive and behavioural change in DLB/PDD. 1971 Nov 17


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