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1.
Depress Anxiety ; 37(9): 842-850, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32667102

RESUMO

BACKGROUND: Novel technologies make it possible to incorporate pharmacogenetic testing into the medical management of depression. However, previous studies indicate that there may be a subset of subjects who have concerns about genetic testing and may be psychologically vulnerable. If so, pharmacogenetic testing in depressed subjects could negatively impact their mental health and undermine treatment goals. METHODS: In this study, we developed a standardized instrument to assess motivations and attitudes around pharmacogenetic testing in a cohort of 170 depressed Veterans participating in a multi-center clinic trial. RESULTS: Testing reveals that subjects were largely positive about the use of genetic testing to guide pharmacological treatment and help plan their future. Most subjects showed only modest concerns about the impact on family, inability to cope with the results, and fear of discrimination. The severity of depression did not predict the concern expressed about negative outcomes. However, non-Caucasian subjects were more likely on average to endorse concerns about poor coping and fear of discrimination. CONCLUSIONS: These data indicate that while the overall risk is modest, some patients with depression may face psychosocial challenges in the context of pharmacogenetic testing. Future work should identify factors that predict distress and aim to tailor test results to different populations.


Assuntos
Transtorno Depressivo Resistente a Tratamento , Testes Farmacogenômicos , Atitude , Depressão , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/genética , Testes Genéticos , Humanos , Motivação
2.
EMBO J ; 29(2): 482-95, 2010 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-19942860

RESUMO

Central noradrenergic signalling mediates arousal and facilitates learning through unknown molecular mechanisms. Here, we show that the beta(2)-adrenergic receptor (beta(2)AR), the trimeric G(s) protein, adenylyl cyclase, and PKA form a signalling complex with the AMPA-type glutamate receptor subunit GluR1, which is linked to the beta(2)AR through stargazin and PSD-95 and their homologues. Only GluR1 associated with the beta(2)AR is phosphorylated by PKA on beta(2)AR stimulation. Peptides that interfere with the beta(2)AR-GluR1 association prevent this phosphorylation of GluR1. This phosphorylation increases GluR1 surface expression at postsynaptic sites and amplitudes of EPSCs and mEPSCs in prefrontal cortex slices. Assembly of all proteins involved in the classic beta(2)AR-cAMP cascade into a supramolecular signalling complex and thus allows highly localized and selective regulation of one of its major target proteins.


Assuntos
Adenilil Ciclases/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Receptores de AMPA/análise , Receptores de AMPA/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Adenilil Ciclases/análise , Animais , Canais de Cálcio/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/análise , Proteína 4 Homóloga a Disks-Large , Eletrofisiologia , Subunidades alfa Gs de Proteínas de Ligação ao GTP/análise , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/genética , Receptores Adrenérgicos beta 2/análise
3.
Front Synaptic Neurosci ; 16: 1291262, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38660466

RESUMO

Rapid, synapse-specific neurotransmission requires the precise alignment of presynaptic neurotransmitter release and postsynaptic receptors. How postsynaptic glutamate receptor accumulation is induced during maturation is not well understood. We find that in cultures of dissociated hippocampal neurons at 11 days in vitro (DIV) numerous synaptic contacts already exhibit pronounced accumulations of the pre- and postsynaptic markers synaptotagmin, synaptophysin, synapsin, bassoon, VGluT1, PSD-95, and Shank. The presence of an initial set of AMPARs and NMDARs is indicated by miniature excitatory postsynaptic currents (mEPSCs). However, AMPAR and NMDAR immunostainings reveal rather smooth distributions throughout dendrites and synaptic enrichment is not obvious. We found that brief periods of Ca2+ influx through NMDARs induced a surprisingly rapid accumulation of NMDARs within 1 min, followed by accumulation of CaMKII and then AMPARs within 2-5 min. Postsynaptic clustering of NMDARs and AMPARs was paralleled by an increase in their mEPSC amplitudes. A peptide that blocked the interaction of NMDAR subunits with PSD-95 prevented the NMDAR clustering. NMDAR clustering persisted for 3 days indicating that brief periods of elevated glutamate fosters permanent accumulation of NMDARs at postsynaptic sites in maturing synapses. These data support the model that strong glutamatergic stimulation of immature glutamatergic synapses results in a fast and substantial increase in postsynaptic NMDAR content that required NMDAR binding to PSD-95 or its homologues and is followed by recruitment of CaMKII and subsequently AMPARs.

4.
Hum Mol Genet ; 19(1): 196-208, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19846466

RESUMO

Premutation CGG repeat expansions (55-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene give rise to the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency and neurodevelopmental problems. Morphometric analysis of Map2B immunofluorescence reveals that neurons cultured from heterozygous female mice with preCGG repeats in defined medium display shorter dendritic lengths and fewer branches between 7 and 21 days in vitro compared with wild-type (WT) littermates. Although the numbers of synapsin and phalloidin puncta do not differ from WT, preCGG neurons possess larger puncta. PreCGG neurons display lower viability, and express elevated stress protein as they mature. PreCGG neurons have inherently different patterns of growth, dendritic complexity and synaptic architecture discernable early in the neuronal trajectory to maturation, and may reflect a cellular basis for the developmental component of the spectrum of clinical involvement in carriers of premutation alleles. The reduced viability of preCGG neurons is consistent with the mRNA toxicity and neurodegeneration associated with FXTAS.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Hipocampo/anormalidades , Hipocampo/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Neurônios/patologia , Expansão das Repetições de Trinucleotídeos/genética , Animais , Sobrevivência Celular , Dendritos/genética , Dendritos/patologia , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Heterocromatina/metabolismo , Heterozigoto , Camundongos , Neurônios/metabolismo , Faloidina/metabolismo , Terminações Pré-Sinápticas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sinapsinas/metabolismo , Fatores de Tempo
5.
J Neurosci ; 30(2): 449-63, 2010 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-20071509

RESUMO

The tyrosine kinase Pyk2 plays a unique role in intracellular signal transduction by linking Ca(2+) influx to tyrosine phosphorylation, but the molecular mechanism of Pyk2 activation is unknown. We report that Pyk2 oligomerization by antibodies in vitro or overexpression of PSD-95 in PC6-3 cells induces trans-autophosphorylation of Tyr402, the first step in Pyk2 activation. In neurons, Ca(2+) influx through NMDA-type glutamate receptors causes postsynaptic clustering and autophosphorylation of endogenous Pyk2 via Ca(2+)- and calmodulin-stimulated binding to PSD-95. Accordingly, Ca(2+) influx promotes oligomerization and thereby autoactivation of Pyk2 by stimulating its interaction with PSD-95. We show that this mechanism of Pyk2 activation is critical for long-term potentiation in the hippocampus CA1 region, which is thought to underlie learning and memory.


Assuntos
Encéfalo/citologia , Quinase 2 de Adesão Focal/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Sinapses/metabolismo , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Encéfalo/metabolismo , Cálcio/metabolismo , Calmodulina/farmacologia , Linhagem Celular Transformada , Proteína 4 Homóloga a Disks-Large , Inibidores Enzimáticos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Quinase 2 de Adesão Focal/imunologia , Proteínas de Fluorescência Verde/genética , Imunoprecipitação/métodos , Técnicas In Vitro , Ionomicina/farmacologia , Ionóforos/farmacologia , Masculino , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Domínios PDZ/fisiologia , Técnicas de Patch-Clamp/métodos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Bloqueadores dos Canais de Sódio/farmacologia , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacologia , Tetrodotoxina/farmacologia , Transfecção/métodos , Tirosina/metabolismo
6.
J Psychopharmacol ; 35(8): 992-1002, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33938307

RESUMO

BACKGROUND: Pharmacotherapies for depression are often ineffective and treatment-resistant depression (TRD) is common across bipolar disorder (BD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Patient genetic information can be used to predict treatment outcomes. Prospective studies indicate that pharmacogenetic (PGX) tests have utility in the treatment of depression. However, few studies have examined the utility of PGX in other diagnoses typified by depression, or in veterans, a cohort with high rates of medical comorbidity, social stress, and suicide. AIM: To determine the efficacy of genetically guided pharmacological treatment of TRD. METHODS: We conducted an 8-week, prospective, multisite, single-blind study in 182 veterans with TRD including patients with BD, MDD, and PTSD. Subjects were randomly assigned to PGX-guided treatment in which the clinician incorporated PGX information into decision-making, or treatment as usual (TAU). RESULTS: Overall, the PGX group improved marginally faster compared to TAU, but the difference was not statistically significant. Secondary analyses revealed that only PTSD patients showed a potential benefit from PGX testing. Patients predicted by PGX testing to have moderate levels of genetic risk showed a significant benefit from the PGX-guided treatment, whereas other risk groups demonstrated no benefit. Clinicians generally found the PGX test was useful, particularly in more depressed patients and/or those with more warnings for significant or serious adverse outcomes. Clinicians more often used the results to select a drug, but only rarely to adjust dosing. CONCLUSIONS: The data reveal possible group differences in the utility of PGX testing in veterans with TRD.ClinicalTrials.gov Identifier: NCT04469322.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Testes Farmacogenômicos/métodos , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/administração & dosagem , Transtorno Bipolar/genética , Estudos de Coortes , Transtorno Depressivo Maior/genética , Transtorno Depressivo Resistente a Tratamento/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Estudos Prospectivos , Método Simples-Cego , Transtornos de Estresse Pós-Traumáticos/genética , Resultado do Tratamento , Veteranos , Adulto Jovem
7.
J Neurochem ; 105(4): 1525-35, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18248613

RESUMO

Docosahexaenoic acid (DHA), the most abundant n-3 polyunsaturated fatty acid in the brain, has important functions in the hippocampus. To better understand essential fatty acid homeostasis in this region of the brain, we investigated the contributions of n-3 fatty acid precursors in supplying hippocampal neurons with DHA. Primary cultures of rat hippocampal neurons incorporated radiolabeled 18-, 20-, 22-, and 24-carbon n-3 fatty acid and converted some of the uptake to DHA, but the amounts produced from either [1-14C]alpha-linolenic or [1-14C]eicosapentaenoic acid were considerably less than the amounts incorporated when the cultures were incubated with [1-14C]22:6n-3. Most of the [1-14C]22:6n-3 uptake was incorporated into phospholipids, primarily ethanolamine phosphoglycerides. Additional studies demonstrated that the neurons converted [1-14C]linoleic acid to arachidonic acid, the main n-6 fatty acid in the brain. These findings differ from previous results indicating that cerebral and cerebellar neurons cannot convert polyunsaturated fatty acid precursors to DHA or arachidonic acid. Fatty acid compositional analysis demonstrated that the hippocampal neurons contained only 1.1-2.5 mol% DHA under the usual low-DHA culture conditions. The relatively low-DHA content suggests that some responses obtained with these cultures may not be representative of neuronal function in the brain.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Ômega-3/biossíntese , Hipocampo/metabolismo , Neurônios/metabolismo , Animais , Células Cultivadas , Ácidos Docosa-Hexaenoicos/análise , Ácidos Graxos Ômega-3/análise , Ácidos Graxos Ômega-3/genética , Hipocampo/química , Neurônios/química , Ratos , Ratos Sprague-Dawley
8.
J Neurosci Methods ; 171(2): 239-47, 2008 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-18471889

RESUMO

In vitro culturing of primary neurons is a mainstay of neurobiological research. Many of these culture paradigms have taken advantage of defined culture media rather than serum additives that contain undefined survival factors to facilitate experimental manipulations and interpretation of the results. To culture neurons in the absence of serum, defined supplements such as B27 are now widely used. However, commercially available supplements exhibit large variability in their capabilities to support neurons in culture. We re-optimized and modified earlier published formulations of B27 using 21 different ingredients (NS21). NS21 supports neuronal cultures of high quality as manifested by their morphological characteristics, formation of synapses, and postsynaptic responses. Much of the variability in the quality of B27/NS21 was due to variability in the quality of different sources of bovine serum albumin. Furthermore, we found that holo-transferrin used in NS21 is preferable over apo-transferrin used in B27 for the quality of neuronal cultures.


Assuntos
Técnicas de Cultura de Células , Meios de Cultura/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Células Cultivadas , Meios de Cultura Livres de Soro , Proteína 4 Homóloga a Disks-Large , Agonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Gânglios Espinais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/citologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Técnicas de Patch-Clamp/métodos , Ratos , Ratos Sprague-Dawley , Retina/citologia , Sinaptotagminas/metabolismo , Fatores de Tempo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia
9.
Trends Pharmacol Sci ; 26(12): 645-53, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16253351

RESUMO

Ca2+ influx through the NMDA receptor and subsequent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) are crucial for learning and one of its physiological correlates, long-term potentiation (LTP). Ca2+/calmodulin promotes CaMKII binding to several postsynaptic proteins, including the NMDA receptor. These interactions strategically place CaMKII at locations where Ca2+ influx through the NMDA receptor is highest for further activation of CaMKII and for phosphorylation of nearby AMPA receptors and of other proteins that are important for LTP. Ca2+-dependent postsynaptic CaMKII clustering is of specific interest because LTP is synapse specific: only synapses that experience LTP-inducing high-frequency activity exhibit LTP. Ca2+-driven protein binding ensures that CaMKII accumulates only at those synapses undergoing LTP. This selectivity is economical and could contribute to the synapse specificity of LTP because downstream effects of CaMKII will occur mainly at synapses that accumulate CaMKII. In this article, we provide an overview of recent progress in postsynaptic CaMKII anchoring and discuss its implication in synaptic plasticity and the etiology and potential treatments of neurological diseases.


Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Doenças do Sistema Nervoso/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Humanos , Potenciação de Longa Duração/fisiologia , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/fisiopatologia , Plasticidade Neuronal/fisiologia , Ligação Proteica , Transporte Proteico , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia
10.
Neuropharmacology ; 45(6): 738-54, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14529713

RESUMO

PSD-95 binds to and co-localizes with NMDA receptors at postsynaptic sites. Their co-expression in COS7 cells induces the formation of aggregates containing both proteins. These findings have lead to the hypothesis that PSD-95 helps to cluster NMDA receptors at postsynaptic sites. In addition, PSD-95 binds various regulatory proteins including Src, Pyk2, SynGAP, and nNOS and may recruit signaling proteins to NMDA receptors. We tested whether synaptic transmission or plasticity was affected by acute dissociation of the PSD-95-NMDA receptor interaction with various peptides that bound to the first two PDZ domains of PSD-95 and its homologs and with antibodies directed against the very C-terminus of the NR2A and NR2B subunits of the NMDA receptor. Membrane-impermeable peptides injected via whole cell patch electrodes distributed within minutes throughout dendritic branches into spines in acute hippocampal slices and membrane-permeable peptides containing 11 arginine residues effectively accumulated in neurites in slices and primary hippocampal cultures. Neither peptides nor antibodies showed any effect on basal synaptic transmission or induction of long-term potentiation (LTP) in hippocampal slices. Pharmacologically isolated NMDA receptor activity was also not affected. However, the membrane-permeable peptide disrupted the NMDA receptor-PSD-95 interaction in slices as tested by immunoprecipitation and subsequent immunoblotting. These findings suggest that acute dissociation of PSD-95 and its homologs from the NMDA receptor and likely from other protein complexes does not result in any easily detectable physiological effects in hippocampal slices. However, we cannot exclude a role of PSD-95 in early events that lead to clustering of NMDA receptors or of other proteins including stargazin and AMPA receptors at postsynaptic sites nor do these experiments address the possibility of long-term changes in the slices. In fact, incubation of primary hippocampal cultures with the membrane-permeable peptide lead to a moderate decrease in the number of dendritic clusters of PSD-95 and NMDA receptors and their colocalization by 20-30%, suggesting some role of PSD-95 and its homologs in NMDA receptor clustering.


Assuntos
Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Células Cultivadas , Proteína 4 Homóloga a Disks-Large , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana , Proteínas do Tecido Nervoso/genética , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Fatores de Tempo
11.
Neuroreport ; 15(5): 829-32, 2004 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-15073524

RESUMO

Dendritic spines, which are the preferred site of excitatory synapses in the mammalian CNS, are actin-rich structures. We hypothesized that dynamic regulation of actin in spines would differentially affects processes that lead to potentiation vs depression of synaptic efficacy. Here, we report that the expression of long-term depression of excitatory synaptic transmission persists in the presence of actin polymerization in rat hippocampal slices. We observe that the reversal of LTD, de-depression, by high-frequency stimulation was completely blocked. Using electron microscopy, dramatic changes in dendritic spine morphology which accompany the sustained, irreversible depression of excitatory synaptic transmission were observed.


Assuntos
Actinas/fisiologia , Dendritos/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Citocalasina D/farmacologia , Dendritos/efeitos dos fármacos , Dendritos/efeitos da radiação , Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Técnicas In Vitro , Masculino , Microscopia Eletrônica/métodos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/efeitos da radiação , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Neurônios/ultraestrutura , Inibidores da Síntese de Ácido Nucleico/farmacologia , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/efeitos da radiação , Tiazóis/farmacologia , Tiazolidinas
12.
Vision Res ; 42(7): 865-71, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11927351

RESUMO

Three monkeys were trained successively with discrimination, concurrent matching to sample, and sameness-difference judgment tasks in which learning curves were compared. Then, the display duration for the stimuli was shortened to 100, 50, and 30 ms respectively to test the changes in accuracy and reaction time. All results in three experimental paradigms suggested consistently that the geometric shape (triangle, circle, and square) plays a more predominant role than topological features (the hole inside of a figure and the hole numbers) in monkey figure recognition. The results are different from the experiment by human subjects who presented hole predominant in figure recognition. Therefore, the precedence in perception depends on subject species, stimulus set, and ecological significance of the perceiving process.


Assuntos
Percepção de Forma , Macaca mulatta/psicologia , Reconhecimento Visual de Modelos , Reconhecimento Psicológico , Animais , Aprendizagem por Discriminação , Feminino , Humanos , Estimulação Luminosa/métodos , Tempo de Reação , Especificidade da Espécie
13.
Vision Res ; 42(7): 873-82, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11927352

RESUMO

The discriminative tasks of face and geometrical figure were trained in three rhesus monkeys. The hole feature speeds up learning of face discrimination, but hampers learning of figure discrimination. By reducing presentation duration of the stimuli, the detecting precedence appears to be the hole feature of the face component, while it appears to be shape feature of figures. The patterns of neuron firings in inferior temporal cortex (IT) are consistent with the context-dependent precedence of hole feature. The results might suggest that the neural correlates exist not only in IT neurons, but also in combination with executive mechanism.


Assuntos
Aprendizagem por Discriminação/fisiologia , Face , Macaca mulatta/psicologia , Neurônios/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Animais , Feminino , Macaca mulatta/fisiologia , Estimulação Luminosa/métodos , Reconhecimento Psicológico/fisiologia , Lobo Temporal/fisiologia , Fatores de Tempo
14.
J Biol Chem ; 283(52): 36241-8, 2008 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-18940801

RESUMO

The neurodegenerative disorder spinocerebellar ataxia 12 (SCA12) is caused by CAG repeat expansion in the non-coding region of the PPP2R2B gene. PPP2R2B encodes Bbeta1 and Bbeta2, alternatively spliced and neuron-specific regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme. We show here that in PC12 cells and hippocampal neurons, cell stressors induced a rapid translocation of PP2A/Bbeta2 to mitochondria to promote apoptosis. Conversely, silencing of PP2A/Bbeta2 protected hippocampal neurons against free radical-mediated, excitotoxic, and ischemic insults. Evidence is accumulating that the mitochondrial fission/fusion equilibrium is an important determinant of cell survival. Accordingly, we found that Bbeta2 expression induces mitochondrial fragmentation, whereas Bbeta2 silencing or inhibition resulted in mitochondrial elongation. Based on epistasis experiments involving Bcl2 and core components of the mitochondrial fission machinery (Fis1 and dynamin-related protein 1), mitochondrial fragmentation occurs upstream of apoptosis and is both necessary and sufficient for hippocampal neuron death. Our data provide the first example of a proapoptotic phosphatase that predisposes to neuronal death by promoting mitochondrial division and point to a possible imbalance of the mitochondrial morphogenetic equilibrium in the pathogenesis of SCA12.


Assuntos
Proteínas de Transporte/fisiologia , Mitocôndrias/metabolismo , Neurônios/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/fisiologia , Ataxias Espinocerebelares/genética , Animais , Apoptose , Proteínas de Transporte/biossíntese , Sobrevivência Celular , Epistasia Genética , Hipocampo/metabolismo , Isquemia , Modelos Biológicos , Células PC12 , Proteína Fosfatase 2/metabolismo , RNA/metabolismo , Ratos , Rotenona/farmacologia
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