RESUMO
A new in vitro model of Huntington's disease (HD) was developed via a direct reprogramming of dermal fibroblasts from HD patients into striatal neurons. A reprogramming into induced pluripotent stem (iPS) cells is obviated in the case of direct reprogramming, which thus yields neurons that preserve the epigenetic information inherent in cells of a particular donor and, consequently, the age-associated disease phenotype. A main histopathological feature of HD was reproduced in the new model; i.e., aggregates of mutant huntingtin accumulated in striatal neurons derived from a patient's fibroblasts. Experiments with cultured neurons obtained via direct reprogramming make it possible to individually assess the progression of neuropathology and to implement a personalized approach to choosing the treatment strategy and drugs for therapy. The in vitro model of HD can be used in preclinical drug studies.
Assuntos
Doença de Huntington , Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Doença de Huntington/genética , Doença de Huntington/patologia , Neurônios , Corpo Estriado/patologia , Fibroblastos , Células-Tronco Pluripotentes Induzidas/patologia , Modelos Animais de DoençasRESUMO
Huntington's disease is a hereditary neurodegenerative disease that primarily affects striatal neurons. Recent studies demonstrated abnormalities in calcium regulation in striatal neurons in Huntington's disease, which leads to elimination of synaptic connections between cortical and striatal neurons. In the present study, we focused on the neuroprotective properties of σ1-receptor, because one of its main functions is associated with modulation of calcium homeostasis in cells. The application of selective σ1-receptor agonists to the corticostriatal cell culture restores synaptic connections between the cortical and striatal neurons. Based on the obtained data, we assume that σ1-receptor is a promising target for the development of drugs for the therapy of Huntington's disease.
Assuntos
Cálcio/metabolismo , Doença de Huntington/genética , Neurônios/metabolismo , Receptores sigma/genética , Transmissão Sináptica/genética , Animais , Anisóis/farmacologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Corpo Estriado/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Expressão Gênica , Homeostase , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Masculino , Camundongos , Modelos Biológicos , Morfolinas/farmacologia , Neurônios/patologia , Piperidinas/farmacologia , Cultura Primária de Células , Propilaminas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Sinapses/metabolismo , Sinapses/patologia , Transdução Genética , Receptor Sigma-1RESUMO
On the page 553 Acknowledgements should be as follows: The study was supported by the Russian Science Foundation (grant 14-25-00024-P).
RESUMO
In primary culture of mouse hippocampal neurons, peptide EDR (200 ng/ml) under conditions of amyloid synaptotoxicity (a model of Alzheimer's disease) increased the number of mushroom spines by 71% and returned this parameter to the normal level. Under the same conditions, tripeptide KED (200 ng/ml) increased the number of mushroom spines in hippocampal neurons by 20%. Tripeptide EDR can be recommended for further experimental study as a candidate neuroprotective agent for prevention and treatment of Alzheimer's disease.
