RESUMO
Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, N-acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone's effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone's effect on OCR parameters is compatible with lithium's known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells.
Assuntos
Autofagia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Trifosfato de Adenosina/metabolismo , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Suscetibilidade a Doenças , Complexo I de Transporte de Elétrons/metabolismo , Humanos , Fosforilação OxidativaRESUMO
The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of "complex disorders". This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders).
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Inflamação/complicações , Transtornos Mentais/etiologia , Neoplasias/etiologia , Neurônios/patologia , Animais , Diabetes Mellitus Tipo 2/patologia , Humanos , Transtornos Mentais/patologia , Neoplasias/patologiaRESUMO
Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug's neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium's neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug's inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium's neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer's disease (AD) and in patients, discussing the rationale for the drug's use in the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Autofagia/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Lítio/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Reposicionamento de Medicamentos , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Lítio/farmacologia , Lítio/toxicidade , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/metabolismoRESUMO
Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin (mTOR) inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively. The results show that rapamycin reduced mania-like aggression and reward-seeking behaviors, with no effects on locomotion. Temsirolimus reduced depression-related immobility in the forced-swim test without effects on locomotion in the open field or on anxiety-related measures in the elevated plus maze. Taken together with our previous findings, these data support the notion that enhancing autophagy may have mood-stabilizing effects.
Assuntos
Afeto/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Sirolimo/farmacologia , Agressão/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Antimaníacos/farmacologia , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sirolimo/análogos & derivadosRESUMO
BACKGROUND: Glycogen synthase kinase-3 (GSK-3) inhibition by lithium has been well established in vitro, but proof that this biochemical effect mediates lithium's beneficial action in patients with bipolar disorder is lacking. We studied whether lymphocyte GSK-3ß activity measured indirectly in lithium- or valproate (VPA)-treated euthymic patients with bipolar disorder is different from controls. METHODS: Lymphocyte total and Ser-9-phospho-GSK-3ß (inactive) levels were measured by Western blotting. Forty-seven patients with bipolar disorder and 32 age- and sex-matched control subjects were studied. RESULTS: No significant differences were found between lithium- and VPA-treated patients and controls in phospho-GSK-3ß, total GSK-3ß, or their ratio. CONCLUSIONS: The data do not support the concept that in vivo, during chronic treatment of bipolar illness, GSK-3ß is inhibited either by lithium or by VPA.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Compostos de Lítio/farmacologia , Linfócitos/efeitos dos fármacos , Ácido Valproico/farmacologia , Adulto , Antimaníacos/administração & dosagem , Feminino , Humanos , Compostos de Lítio/administração & dosagem , Linfócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Ácido Valproico/administração & dosagemRESUMO
Lithium treatment in rodents markedly enhances cholinergic agonists such as pilocarpine. This effect can be reversed in a stereospecific manner by administration of inositol, suggesting that the effect of lithium is caused by inositol monophosphatase inhibition and consequent inositol depletion. If so, inositol-deficient food would be expected to enhance lithium effects. Inositol-deficient food was prepared from inositol-free ingredients. Mice with a homozygote knockout of the inositol monophosphatase 1 gene unable to synthesize inositol endogenously and mimicking lithium-treated animals were fed this diet or a control diet. Lithium-treated wild-type animals were also treated with the inositol-deficient diet or control diet. Pilocarpine was administered after 1 week of treatment, and behavior including seizures was assessed using rating scale. Inositol-deficient food-treated animals, both lithium treated and with inositol monophosphatase 1 knockout, had significantly elevated cholinergic behavior rating and significantly increased or earlier seizures compared with the controls. The effect of inositol-deficient food supports the role of inositol depletion in the effects of lithium on pilocarpine-induced behavior. However, the relevance of this behavior to other more mood-related effects of lithium is not clear.
Assuntos
Antimaníacos/uso terapêutico , Comportamento/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Inositol/deficiência , Compostos de Lítio/uso terapêutico , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Deficiência de Vitaminas do Complexo B/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/psicologia , Dieta , Inibidores Enzimáticos/farmacologia , Camundongos , Camundongos Endogâmicos ICR , PilocarpinaRESUMO
OBJECTIVE: The underlying biology of bipolar disorder and the mechanisms by which effective medications induce their therapeutic effects are not clear. Appropriate use of animal models are essential to further understand biological mechanisms of disease and treatment, and further understanding the therapeutic mechanism of mood stabilisers requires that clinically relevant administration will be effective in animal models. The clinical regimens for mood-stabilising drugs include chronic oral administration; however, much of the work with animal models includes acute administration via injection. An effective chronic and oral administration of the prototypic mood stabiliser lithium was already established and the present study was designed to do the same for the mood stabiliser carbamazepine. METHODS: Mice were treated for 3 weeks with carbamazepine in food. ICR mice were treated with 0.25%, 0.5% and 0.75%, and C57bl/6 mice with 0.5% and 0.75%, carbamazepine in food (w/w, namely, 2.5, 5.0 or 7.5 g/kg food). Mice were then tested for spontaneous activity, forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperactivity. RESULTS: Oral carbamazepine administration resulted in dose-dependent blood levels reaching 3.65 µg/ml at the highest dose. In ICR mice, carbamazepine at the 0.5% dose had no effect on spontaneous activity, but significantly reduced immobility in the TST by 27% and amphetamine-induced hyperactivity by 28%. In C57bl/6 mice, carbamazepine at the 0.75% dose reduced immobility time in the FST by 26%. CONCLUSIONS: These results demonstrate a behaviourally effective oral and chronic regimen for carbamazepine with mood stabilising-like activity in a standard model for mania-like behaviour and two standard models for depression-like behaviour.
Assuntos
Afeto/efeitos dos fármacos , Carbamazepina/administração & dosagem , Administração Oral , Animais , Transtorno Bipolar/tratamento farmacológico , Carbamazepina/sangue , Carbamazepina/uso terapêutico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Atividade MotoraRESUMO
Stress is a common denominator of complex disorders and the FK-506 binding protein (FKBP)51 plays a central role in stress. Hence, it is not surprising that multiple studies imply the involvement of the FKBP51 protein and/or its coding gene, FKBP5, in complex disorders. This review summarizes such reports concentrating on three disorder clusters-neuropsychiatric, cancer, and type 2 diabetes mellitus (T2DM). We also attempt to point to potential mechanisms suggested to mediate the effect of FKBP5/FKBP51 on these disorders. Neuropsychiatric diseases considered in this paper include (i) Huntington's disease for which increased autophagic cellular clearance mechanisms related to decreased FKBP51 protein levels or activity is discussed, Alzheimer's disease for which increased FKBP51 activity has been shown to induce Tau phosphorylation and aggregation, and Parkinson's disease in the context of which FKBP12 is mentioned; and (ii) mental disorders, for which significant association with the single nucleotide polymorphism (SNP) rs1360780 of FKBP5 intron 7 along with decreased DNA methylation were revealed. Since cancer is a large group of diseases that can start in almost any organ or tissue of the body, FKBP51's role depends on the tissue type and differences among pathways expressed in those tumors. The FKBP51-heat-shock protein-(Hsp)90-p23 super-chaperone complex might function as an oncogene or as a tumor suppressor by downregulating the serine/threonine protein kinase (AKt) pathway. In T2DM, two potential pathways for the involvement of FKBP51 are highlighted as affecting the pathogenesis of the disease-the peroxisome proliferator-activated receptor-γ (PPARγ) and AKt.
Assuntos
Diabetes Mellitus Tipo 2 , Transtornos Mentais , Neoplasias , Proteínas de Ligação a Tacrolimo , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Proteínas de Ligação a Tacrolimo/genética , Neoplasias/genética , Neoplasias/metabolismo , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , AnimaisRESUMO
Individual differences in response to pharmacologic treatment limits the usefulness of mean data obtained from randomized controlled trials. These individual differences exist even in genetically uniform inbred mouse strains. While stratification can be of value in large studies, the individual patient history is the most effective currently available guide for personalized medicine in psychopharmacology.
Assuntos
Individualidade , Transtornos Mentais/tratamento farmacológico , Psicofarmacologia/métodos , Psicotrópicos/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Humanos , Camundongos , Psicotrópicos/farmacologia , Resultado do TratamentoRESUMO
Emerging evidence suggests impaired one-carbon metabolism in schizophrenia. Homocysteine is one of the key components of one-carbon metabolism. Elevated plasma homocysteine levels were reported in schizophrenia. A linkage study found that nicotinamide-N-methyltransferase (NNMT), an enzyme involved in one-carbon metabolism, is a determinant of plasma homocysteine levels. In an association study the rs694539 NNMT single nucleotide polymorphism (SNP) was found significantly associated with hyperhomocysteinaemia. Aiming to assess the possible involvement of NNMT in the aetiology of schizophrenia we (1) performed an association study of eight NNMT tagged SNPs in 202 families sharing the same ethnic origin including healthy parents and a schizophrenia proband; (2) assessed NNMT mRNA levels in post-mortem frontal cortex of schizophrenia patients. Genotyping was performed using the ABI SNaPshot and the HRM methods. Individual SNPs and haplotypes were analysed for association using the family-based association test (UNPHASED software). NNMT mRNA levels were measured using RT real-time PCR. In the single SNP analysis, rs694539, previously reported to be associated with hyperhomocysteinaemia, and rs1941404 were significantly associated with schizophrenia (p<0.004 and p=0.033, respectively, following permutation test adjustment). Several haplotypes were also significantly associated with schizophrenia (global p values <0.05 following permutation test adjustment). This is the first study demonstrating an association of NNMT with schizophrenia. Post-mortem frontal cortex NNMT mRNA levels were ~35% lower in schizophrenia patients vs. control subjects. Our study favours the notion that NNMT is involved in the aetiology of schizophrenia.
Assuntos
Lobo Frontal/metabolismo , Nicotinamida N-Metiltransferase/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/metabolismo , Esquizofrenia/genética , Esquizofrenia/patologia , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Nicotinamida N-Metiltransferase/metabolismo , Adulto JovemRESUMO
Several studies of normobaric hyperoxia in neurological conditions have found positive results. The impaired energy metabolism due to mitochondrial dysfunction and frontal lobe hypofunction in schizophrenia might be improved by increasing O2 supply to the brain. Normobaric hyperoxia may be a potential treatment for schizophrenia. Participants in this study, outpatients with chronic schizophrenia and inhabitants of community-based psychiatric institutions (hostels), underwent baseline psychiatric/cognitive assessment and were randomly assigned to either a treatment intervention of oxygen-enriched air inhalation (normobaric hyperoxia of 40% fraction of inspired oxygen) or regular air inhalation (21% fraction of inspired oxygen), through a nasal tube, for 4 weeks. Patients were given the air/oxygen inhalations during the night (mainly while sleeping) for at least 7 hours a night. After completing 4 weeks of treatment, patients were switched (crossed over) to the other treatment intervention. Fifteen patients completed the entire study. Five additional patients completed phase A only. There was significant improvement in total Positive and Negative Symptoms Scale score of patients who received oxygen compared with the control group. There were positive effects of oxygen on memory and attention in neuropsychological performance tests. The effect size is small despite the statistical significance, but the patient group was extremely chronic and severely impaired. These results are a proof of concept, and normobaric hyperoxia should be studied in patients with milder forms of the illness and earlier in the course of illness.
Assuntos
Hiperóxia/psicologia , Oxigenoterapia/psicologia , Esquizofrenia/terapia , Psicologia do Esquizofrênico , Adulto , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Oxigenoterapia/métodos , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Desempenho PsicomotorRESUMO
Multiple studies imply a strong relationship between global warming (GW) and complex disorders. This review summarizes such reports concentrating on three disorders-mental disorders (MD), primary hypertension, and type 2 diabetes (T2D). We also attempt to point at potential mechanisms mediating the effect of GW on these disorders. Concerning mental disorders, immediate candidates are brain levels of heat-shock proteins (HSPs). In addition, given that heat stress increases reactive oxygen species (ROS) levels which may lead to blood-brain barrier (BBB) breakdown and, hence, enhanced protein extravasation in the brain, this might finally cause, or exacerbate mental health. As for hypertension, since its causes are incompletely understood, the mechanism(s) by which heat exposure affects blood pressure (BP) is an open question. Since the kidneys participate in regulating blood volume and BP they are considered as a site of heat-associated disease, hence, we discuss hyperosmolarity as a potential mediator. In addition, we relate to autoimmunity, inflammation, sodium excretion, and HSP70 as risk factors that might play a role in the effect of heat on hypertension. In the case of T2D, we raise two potential mediators of the effect of exposure to ambient hot environment on the disease's incidence-brown adipose tissue metabolism and HSPs.
Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Transtornos Mentais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Aquecimento Global , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Hipertensão/etiologia , Transtornos Mentais/complicaçõesRESUMO
Mounting evidence suggests that immune-system dysfunction and inflammation play a role in the pathophysiology and treatment of mood-disorders in general and of bipolar disorder in particular. The current study examined the effects of chronic low-dose aspirin and low-dose lithium (Li) treatment on plasma and brain interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-treated rats. Rats were fed regular or Li-containing food (0.1%) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. On days 21 and 42 rats were injected with 1 mg/kg LPS or saline. Two h later body temperature was measured and rats were sacrificed. Blood samples, the frontal-cortex, hippocampus, and the hypothalamus were extracted. To assess the therapeutic potential of the combined treatment, rats were administered the same Li + aspirin protocol without LPS. We found that the chronic combined treatment attenuated LPS-induced hypothermia and significantly reduced plasma and brain cytokine level elevation, implicating the potential neuroinflammatory diminution purportedly present among the mentally ill. The combined treatment also significantly decreased immobility time and increased struggling time in the forced swim test, suggestive of an antidepressant-like effect. This preclinical evidence provides a potential approach for treating inflammation-related mental illness.
Assuntos
Transtorno Bipolar , Lítio , Antimaníacos , Quinase 3 da Glicogênio Sintase , Humanos , FosforilaçãoRESUMO
Inhibition of glycogen synthase kinase-3 (GSK-3) is thought to be a major consequence of the biological and clinical activity of the mood stabilizer lithium, however, lithium and GSK-3 may activate distinct cellular pathways. We employed a proteomic method to uncover new downstream targets of lithium, and then examined how these proteins are related to GSK-3. Proteomic analysis identified eukaryotic elongation factor-2 (eEF-2) as a cellular target of lithium. This was verified in SH-SY5Y cells and animal models. In cells, lithium decreased eEF-2 phosphorylation at its key inhibitory site, threonine 56, and blocked the enhancement of eEF-2 phosphorylation normally coupled with stress conditions such as nutrient and serum deprivation. Unexpectedly, inhibition of GSK-3 enhanced eEF-2 phosphorylation, and overexpression of GSK-3α or GSK-3ß resulted in a strong reduction in eEF-2 phosphorylation. Chronic administration of lithium reduced the hippocampal fraction of phospho-eEF-2 (phospho-eEF-2/total eEF-2) twofold in two different mouse strains. In summary, unexpectedly eEF-2 is activated by both lithium and GSK-3, whereas, lithium treatment and inhibition of GSK-3 have opposing effects on eEF-2.
Assuntos
Antidepressivos/farmacologia , Quinase do Fator 2 de Elongação/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/efeitos dos fármacos , Compostos de Lítio/farmacologia , Animais , Linhagem Celular , Eletroforese em Gel Bidimensional , Quinase do Fator 2 de Elongação/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos ICR , FosforilaçãoRESUMO
Despite established efficacy in bipolar disorder patients, lithium (Li) therapy has serious side effects, particularly chronic kidney disease. We examined the safety and behavioral effects of combined chronic low-dose aspirin plus low-dose Li in rats to explore the toxicity and therapeutic potential of this treatment. Rats were fed regular or Li-containing food (0.1% [low-dose, LLD-Li] or 0.2% [standard-dose, STD-Li]) for six weeks. Low-dose aspirin (1 mg/kg) was administered alone or together with Li. Renal function and gastric mucosal integrity were assessed. The effects of the combination treatment were evaluated in depression-like and anxiety-like behavioral models. Co-treatment with aspirin did not alter plasma Li levels. Chronic STD-Li treatment resulted in significant polyuria and polydipsia, elevated blood levels of creatinine and cystatin C, and increased levels of kidney nephrin and podocin-all suggestive of impaired renal function. Aspirin co-treatment significantly damped STD-Li-induced impairments in kidney parameters. There were no gastric ulcers or blood loss in any treatment group. Combined aspirin and LLD-Li resulted in a significant increase in sucrose consumption, and in the time spent in the open arms of an elevated plus-maze compared with the LLD-Li only group, suggestive of antidepressant-like and anxiolytic-like effects, respectively. Thus, we demonstrate that low-dose aspirin mitigated the typical renal side effects of STD-Li dose and enhanced the beneficial behavioral effects of LLD-Li therapy without aggravating its toxicity.
RESUMO
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Assuntos
Autofagia , Animais , Autofagossomos , Autofagia/fisiologia , Proteínas Relacionadas à Autofagia/metabolismo , Bioensaio/normas , Biomarcadores , Humanos , LisossomosRESUMO
BACKGROUND: Schizophrenia is associated with rare copy-number (CN) mutations. Screening for such alleles genome-wide, though comprehensive, cannot study in-depth the causality of particular loci, therefore cannot provide the functional interpretation for the disease etiology. We hypothesized that CN mutations in the SELENBP1 locus could associate with the disorder and that these mutations could alter the gene product's activity in patients. METHODS: We analyzed SELENBP1 CN variation (CNV) in blood DNA from 49 schizophrenia patients and 49 controls (cohort A). Since CN of genes may vary among tissues, we investigated SELENBP1 CN in age- sex- and postmortem interval-matched cerebellar DNA samples from 14 patients and 14 controls (cohort B). Since CNV may either be de-novo or inherited we analyzed CNV of the SELENBP1 locus in blood DNA from 26 trios of schizophrenia probands and their healthy parents (cohort C). SELENBP1 mRNA levels were measured by real-time PCR. RESULTS: In cohort A reduced CN of the SELENBP1 locus was found in four patients but in none of the controls. In cohort B we found reduced CN of the SELENBP1 locus in two patients but in none of the controls. In cohort C three patients exhibited drastic CN reduction, not present in their parents, indicating de-novo mutation. A reduction in SELENBP1 mRNA levels in the postmortem cerebellar samples of schizophrenia patients was found. CONCLUSIONS: We report a focused study of CN mutations in the selenium binding-protein1 (SELENBP1) locus previously linked with schizophrenia. We provide evidence for recurrence of decreased CN of the SELENBP1 locus in three unrelated patients' cohorts but not in controls, raising the possibility of functional involvement of these mutations in the etiology of the disease.
Assuntos
Cerebelo/metabolismo , Variações do Número de Cópias de DNA , Esquizofrenia/genética , Esquizofrenia/metabolismo , Proteínas de Ligação a Selênio/genética , Proteínas de Ligação a Selênio/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Análise de Sequência de DNA , Adulto JovemRESUMO
Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr+/- genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr+/- mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr+/- mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.
Assuntos
Transtorno Autístico , Colina/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2) , Animais , Transtorno Autístico/tratamento farmacológico , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Camundongos , Fenótipo , Comportamento SocialRESUMO
Pharmacological treatment of mental disorders is currently decided based on "trial and error" strategy. Mitochondrial multifaceted dysfunction is assumed to be a major factor in the pathophysiology and treatment of schizophrenia (SZ) and bipolar disorder (BD). This study aimed to explore the feasibility of using a profile of mitochondrial function parameters as a tool to predict the optimal drug for an individual patient (personalized medicine). Healthy controls (n = 40), SZ (n = 48) and BD (n = 27) patients were recruited. Mental and global state of the subjects, six mitochondrial respiration parameters and 14 mitochondrial function-related proteins were assessed in fresh lymphocytes following in-vitro or in-vivo treatment with five antipsychotic drugs and two mood-stabilizers. In healthy controls, hierarchal clustering shows a drug-specific effect profile on the different mitochondrial parameters following in-vitro exposure. Similar changes were observed in untreated SZ and BD patients with psychosis. Following a month of treatment of the latter patients, only responders showed a significant correlation between drug-induced in-vitro effect (prior to in-vivo treatment) and short-term in-vivo treatment effect for 45% of the parameters. Long- but not short-term psychotropic treatment normalized mitochondria-related parameters in patients with psychosis. Taken together, these data substantiate mitochondria as a target for psychotropic drugs and provide a proof of concept for selective mitochondrial function-related parameters as a predictive tool for an optimized psychotropic treatment in a given patient. This, however, needs to be repeated with an expanded sample size and additional mitochondria related parameters.