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1.
Cell Rep ; 40(9): 111261, 2022 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-36044862

RESUMEN

Compelling evidence indicates that in Huntington's disease (HD), mutation of huntingtin (HTT) alters several aspects of early brain development such as synaptogenesis. It is not clear to what extent the partial loss of wild-type HTT function contributes to these abnormalities. Here we investigate the function of HTT in the formation of spines. Although larger spines normally correlate with more synaptic activity, cell-autonomous depletion of HTT leads to enlarged spines but reduced excitatory synaptic function. We find that HTT is required for the proper turnover of endogenous actin and to recruit AMPA receptors at active synapses; loss of HTT leads to LIM kinase (LIMK) hyperactivation, which maintains cofilin in its inactive state. HTT therefore influences actin dynamics through the LIMK-cofilin pathway. Loss of HTT uncouples spine structure from synaptic function, which may contribute to the ultimate development of HD symptoms.


Asunto(s)
Factores Despolimerizantes de la Actina , Espinas Dendríticas , Proteína Huntingtina , Citoesqueleto de Actina/metabolismo , Factores Despolimerizantes de la Actina/metabolismo , Actinas/metabolismo , Animales , Espinas Dendríticas/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/metabolismo , Ratones , Sinapsis/metabolismo
2.
Neuron ; 110(1): 36-50.e5, 2022 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-34793694

RESUMEN

Although the classic symptoms of Huntington's disease (HD) manifest in adulthood, neural progenitor cell behavior is already abnormal by 13 weeks' gestation. To determine how these developmental defects evolve, we turned to cell and mouse models. We found that layer II/III neurons that normally connect the hemispheres are limited in their growth in HD by microtubule bundling defects within the axonal growth cone, so that fewer axons cross the corpus callosum. Proteomic analyses of the growth cones revealed that NUMA1 (nuclear/mitotic apparatus protein 1) is downregulated in HD by miR-124. Suppressing NUMA1 in wild-type cells recapitulates the microtubule and axonal growth defects of HD, whereas raising NUMA1 levels with antagomiR-124 or stabilizing microtubules with epothilone B restores microtubule organization and rescues axonal growth. NUMA1 therefore regulates the microtubule network in the growth cone, and HD, which is traditionally conceived as a disease of intracellular trafficking, also disturbs the cytoskeletal network.


Asunto(s)
Enfermedad de Huntington , Animales , Axones/metabolismo , Proteínas de Ciclo Celular/metabolismo , Conos de Crecimiento/fisiología , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Ratones , Microtúbulos/metabolismo , Proteómica
3.
Science ; 369(6505): 787-793, 2020 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-32675289

RESUMEN

Although Huntington's disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington's disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carried the Huntington's disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington's disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington's disease thus has a neurodevelopmental component and is not solely a degenerative disease.


Asunto(s)
Proteína Huntingtina/metabolismo , Enfermedad de Huntington/metabolismo , Sistema Nervioso/embriología , Animales , Ciclo Celular , Endosomas/metabolismo , Feto , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Ratones , Ratones Mutantes , Mitosis , Mutación , Células Neuroepiteliales/metabolismo , Uniones Estrechas/metabolismo , Proteína de la Zonula Occludens-1/metabolismo
4.
Autophagy ; 13(3): 554-566, 2017 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-28059583

RESUMEN

Macroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and Beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC. Of note, post-transcriptional regulation mediated by noncoding microRNAs (MIRNAs) contributes significantly to control autophagy. Here we describe a new role for the microRNA MIR7-3HG/MIR-7 as a potent autophagy inhibitor. Indeed, MIR7-3HG targets the 3' untranslated region (UTR) of AMBRA1 mRNA, inducing a decrease of both AMBRA1 mRNA and protein levels, and thus causing a block in autophagy. Furthermore, MIR7-3HG, through AMBRA1 downregulation, prevents MYC dephosphorylation, establishing a positive feedback for its own transcription. These data suggest a new and interesting role of MIR7-3HG as an anti-autophagic MIRNA that may affect oncogenesis through the regulation of the tumor suppressor AMBRA1.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autofagia , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Largo no Codificante/metabolismo , Regiones no Traducidas 3'/genética , Células A549 , Proteínas Adaptadoras Transductoras de Señales/genética , Autofagia/genética , Secuencia de Bases , Proliferación Celular/genética , Simulación por Computador , Regulación hacia Abajo/genética , Células HEK293 , Células HeLa , Humanos , Modelos Biológicos , Fosforilación , Fosfoserina/metabolismo , ARN Largo no Codificante/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo
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