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1.
Acta Neuropathol ; 137(6): 961-980, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30927072

RESUMEN

Progressive aggregation of the protein alpha-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are key histopathological hallmarks of Parkinson's disease (PD). Accruing evidence suggests that α-syn pathology can propagate through neuronal circuits in the brain, contributing to the progressive nature of the disease. Thus, it is therapeutically pertinent to identify modifiers of α-syn transmission and aggregation as potential targets to slow down disease progression. A growing number of genetic mutations and risk factors has been identified in studies of familial and sporadic forms of PD. However, how these genes affect α-syn aggregation and pathological transmission, and whether they can be targeted for therapeutic interventions, remains unclear. We performed a targeted genetic screen of risk genes associated with PD and parkinsonism for modifiers of α-syn aggregation, using an α-syn preformed-fibril (PFF) induction assay. We found that decreased expression of Lrrk2 and Gba modulated α-syn aggregation in mouse primary neurons. Conversely, α-syn aggregation increased in primary neurons from mice expressing the PD-linked LRRK2 G2019S mutation. In vivo, using LRRK2 G2019S transgenic mice, we observed acceleration of α-syn aggregation and degeneration of dopaminergic neurons in the SNpc, exacerbated degeneration-associated neuroinflammation and behavioral deficits. To validate our findings in a human context, we established a novel human α-syn transmission model using induced pluripotent stem cell (iPS)-derived neurons (iNs), where human α-syn PFFs triggered aggregation of endogenous α-syn in a time-dependent manner. In PD subject-derived iNs, the G2019S mutation enhanced α-syn aggregation, whereas loss of LRRK2 decreased aggregation. Collectively, these findings establish a strong interaction between the PD risk gene LRRK2 and α-syn transmission across mouse and human models. Since clinical trials of LRRK2 inhibitors in PD are currently underway, our findings raise the possibility that these may be effective in PD broadly, beyond cases caused by LRRK2 mutations.


Asunto(s)
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/fisiología , Mutación Missense , Neuronas/metabolismo , Enfermedad de Parkinson/genética , Agregación Patológica de Proteínas/etiología , alfa-Sinucleína/metabolismo , Amiloide/metabolismo , Animales , Células Cultivadas , Corteza Cerebral/citología , Conducta Exploratoria , Glucosilceramidasa/genética , Hipocampo/citología , Humanos , Células Madre Pluripotentes Inducidas/citología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/deficiencia , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/patología , Enfermedad de Parkinson/patología , Porción Compacta de la Sustancia Negra/patología , Cultivo Primario de Células , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , Interferencia de ARN , Proteínas Recombinantes/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante
2.
Hum Mol Genet ; 25(22): 4920-4938, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-28171570

RESUMEN

Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington's disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75NTR ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signalling while inhibiting c-Jun kinase (JNK) and other degenerative signalling. Normalizing p75NTR signalling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75NTR ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75NTR as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.


Asunto(s)
Enfermedad de Huntington/tratamiento farmacológico , Isoleucina/análogos & derivados , Morfolinas/farmacología , Receptores de Factor de Crecimiento Nervioso/metabolismo , Animales , Modelos Animales de Enfermedad , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Isoleucina/farmacología , Ligandos , Masculino , Ratones , Ratones Transgénicos , Terapia Molecular Dirigida , Fenotipo , Unión Proteica , Distribución Aleatoria , Receptores de Factor de Crecimiento Nervioso/genética , Transducción de Señal/efectos de los fármacos
3.
J Neurosci ; 33(48): 18712-27, 2013 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-24285878

RESUMEN

Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.


Asunto(s)
Benzamidas/uso terapéutico , Enfermedad de Huntington/tratamiento farmacológico , Trastornos del Movimiento/tratamiento farmacológico , Receptor trkB/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Benzamidas/farmacocinética , Western Blotting , Peso Corporal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/fisiología , Espinas Dendríticas/fisiología , Humanos , Proteína Huntingtina , Enfermedad de Huntington/patología , Enfermedad de Huntington/fisiopatología , Inmunohistoquímica , Ligandos , Masculino , Ratones , Ratones Mutantes Neurológicos , Ratones Transgénicos , Trastornos del Movimiento/patología , Trastornos del Movimiento/fisiopatología , Proteínas del Tejido Nervioso/metabolismo , Equilibrio Postural/efectos de los fármacos , ARN/biosíntesis , ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor trkB/fisiología , Transducción de Señal/efectos de los fármacos , Sobrevida
4.
Physiol Behav ; 147: 7-15, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-25846435

RESUMEN

In canaries, specific phrases of male song (sexy songs, SS) that are difficult to produce are especially attractive for females. Females exposed to SS produce more copulation displays and deposit more testosterone into their eggs than females exposed to non-sexy songs (NS). Increased expression of the immediate early genes c-Fos or zenk (a.k.a. egr-1) has been observed in the auditory forebrain of female songbirds hearing attractive songs. C-Fos immunoreactive (Fos-ir) cell numbers were quantified here in the brain of female canaries that had been collected 30min after they had been exposed for 60min to the playback of SS or NS or control white noise. Fos-ir cell numbers increased in the caudomedial mesopallium (CMM) and caudomedial nidopallium (NCM) of SS birds as compared to controls. Song playback (pooled SS and NS) also tended to increase average Fos-ir cell numbers in the mediobasal hypothalamus (MBH) but this effect did not reach full statistical significance. At the individual level, Fos expression in CMM was correlated with its expression in NCM and in MBH but also with the frequency of calls that females produced in response to the playbacks. These data thus indicate that male songs of different qualities induce a differential metabolic activation of NCM and CMM. The correlation between activation of auditory regions and of the MBH might reflect the link between auditory stimulation and changes in behavior and reproductive physiology.


Asunto(s)
Percepción Auditiva/fisiología , Canarios/fisiología , Prosencéfalo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estimulación Acústica , Animales , Recuento de Células , Femenino , Masculino , Prosencéfalo/citología , Psicoacústica , Estadísticas no Paramétricas , Vocalización Animal/fisiología
5.
J Clin Invest ; 123(12): 5371-88, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24231356

RESUMEN

Huntington's disease (HD) is the result of expression of a mutated Huntingtin protein (mtHtt), and is associated with a variety of cellular dysfunctions including excessive mitochondrial fission. Here, we tested whether inhibition of excessive mitochondrial fission prevents mtHtt-induced pathology. We developed a selective inhibitor (P110-TAT) of the mitochondrial fission protein dynamin-related protein 1 (DRP1). We found that P110-TAT inhibited mtHtt-induced excessive mitochondrial fragmentation, improved mitochondrial function, and increased cell viability in HD cell culture models. P110-TAT treatment of fibroblasts from patients with HD and patients with HD with iPS cell-derived neurons reduced mitochondrial fragmentation and corrected mitochondrial dysfunction. P110-TAT treatment also reduced the extent of neurite shortening and cell death in iPS cell-derived neurons in patients with HD. Moreover, treatment of HD transgenic mice with P110-TAT reduced mitochondrial dysfunction, motor deficits, neuropathology, and mortality. We found that p53, a stress gene involved in HD pathogenesis, binds to DRP1 and mediates DRP1-induced mitochondrial and neuronal damage. Furthermore, P110-TAT treatment suppressed mtHtt-induced association of p53 with mitochondria in multiple HD models. These data indicate that inhibition of DRP1-dependent excessive mitochondrial fission with a P110-TAT-like inhibitor may prevent or slow the progression of HD.


Asunto(s)
Dinaminas/antagonistas & inhibidores , GTP Fosfohidrolasas/antagonistas & inhibidores , Enfermedad de Huntington/tratamiento farmacológico , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/antagonistas & inhibidores , Adulto , Animales , Células Cultivadas , Niño , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Fibroblastos , Técnicas de Sustitución del Gen , Células HEK293 , Humanos , Enfermedad de Huntington/patología , Células Madre Pluripotentes Inducidas/patología , Masculino , Ratones , Ratones Transgénicos , Mitocondrias/fisiología , Terapia Molecular Dirigida , Degeneración Nerviosa/prevención & control , Neuritas/ultraestructura , Neurogénesis , Unión Proteica , Proteínas Recombinantes/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
6.
PLoS One ; 8(7): e69233, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23874920

RESUMEN

With the availability and ease of small molecule production and design continuing to improve, robust, high-throughput methods for screening are increasingly necessary to find pharmacologically relevant compounds amongst the masses of potential candidates. Here, we demonstrate that a primary oxygen glucose deprivation assay in primary cortical neurons followed by secondary assays (i.e. post-treatment protocol in organotypic hippocampal slice cultures and cortical neurons) can be used as a robust screen to identify neuroprotective compounds with potential therapeutic efficacy. In our screen about 50% of the compounds in a library of pharmacologically active compounds displayed some degree of neuroprotective activity if tested in a pre-treatment toxicity assay but just a few of these compounds, including Carbenoxolone, remained active when tested in a post-treatment protocol. When further examined, Carbenoxolone also led to a significant reduction in infarction size and neuronal damage in the ischemic penumbra when administered six hours post middle cerebral artery occlusion in rats. Pharmacological testing of Carbenoxolone-related compounds, acting by inhibition of 11-ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1), gave rise to similarly potent in vivo neuroprotection. This indicates that the increase of intracellular glucocorticoid levels mediated by 11ß-HSD1 may be involved in the mechanism that exacerbates ischemic neuronal cell death, and inhibiting this enzyme could have potential therapeutic value for neuroprotective therapies in ischemic stroke and other neurodegenerative disorders associated with neuronal injury.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Fármacos Neuroprotectores/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Análisis de Varianza , Carbenoxolona/farmacología , Descubrimiento de Drogas/métodos , Glucocorticoides/metabolismo , Hipocampo/citología , Humanos , Neuronas/efectos de los fármacos , Propidio , Estadísticas no Paramétricas
7.
Behav Processes ; 82(1): 75-7, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19615614

RESUMEN

Living in social groups presents the opportunity to use information provided by other individuals. Several animal species emit specific vocalizations when they find food. Here, we investigate whether African grey parrots (Psittacus erithacus) use vocal and non-vocal information provided by a conspecific in order to find a hidden food source. One subject was attracted by the presence or the vocalizations of a subordinate conspecific, but not of a dominant, which brings us to hypothesize that parrots could be capable of individual vocal discrimination.


Asunto(s)
Discriminación en Psicología , Dominación-Subordinación , Loros , Vocalización Animal , Animales , Femenino , Masculino , Conducta Social , Análisis y Desempeño de Tareas
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