Patient-derived neuron model: Capturing age-dependent adult-onset degenerative pathology in Huntington's disease.
Mol Cells
; 47(4): 100046, 2024 Apr.
Article
en En
| MEDLINE
| ID: mdl-38492889
ABSTRACT
MicroRNAs play a crucial role in directly reprogramming (converting) human fibroblasts into neurons. Specifically, miR-9/9* and miR-124 (miR-9/9*-124) display neurogenic and cell fate-switching activities when ectopically expressed in human fibroblasts by erasing fibroblast identity and inducing a pan-neuronal state. These converted neurons maintain the biological age of the starting fibroblasts and thus provide a human neuron-based platform to study cellular properties in aged neurons and model adult-onset neurodegenerative disorders using patient-derived cells. Furthermore, the expression of striatal-enriched transcription factors in conjunction with miR-9/9*-124 guides the identity of medium spiny neurons (MSNs), the primary targets in Huntington's disease (HD). Converted MSNs from HD patient-derived fibroblasts (HD-MSNs) can replicate HD-related phenotypes including neurodegeneration associated with age-related declines in critical cellular functions such as autophagy. Here, we review the role of microRNAs in the direct conversion of patient-derived fibroblasts into MSNs and the practical application of converted HD-MSNs as a model for studying adult-onset neuropathology in HD. We provide valuable insights into age-related, cell-intrinsic changes contributing to neurodegeneration in HD-MSNs. Ultimately, we address a comprehensive understanding of the complex molecular landscape underlying HD pathology, offering potential avenues for therapeutic application.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Enfermedad de Huntington
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MicroARNs
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Fibroblastos
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Neuronas
Límite:
Adult
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Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article