Huntingtin lowering impairs the maturation and synchronized synaptic activity of human cortical neuronal networks derived from induced pluripotent stem cells.
Neurobiol Dis
; 200: 106630, 2024 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-39106928
ABSTRACT
Despite growing descriptions of wild-type Huntingtin (wt-HTT) roles in both adult brain function and, more recently, development, several clinical trials are exploring HTT-lowering approaches that target both wt-HTT and the mutant isoform (mut-HTT) responsible for Huntington's disease (HD). This non-selective targeting is based on the autosomal dominant inheritance of HD, supporting the idea that mut-HTT exerts its harmful effects through a toxic gain-of-function or a dominant-negative mechanism. However, the precise amount of wt-HTT needed for healthy neurons in adults and during development remains unclear. In this study, we address this question by examining how wt-HTT loss affects human neuronal network formation, synaptic maturation, and homeostasis in vitro. Our findings establish a role of wt-HTT in the maturation of dendritic arborization and the acquisition of network-wide synchronized activity by human cortical neuronal networks modeled in vitro. Interestingly, the network synchronization defects only became apparent when more than two-thirds of the wt-HTT protein was depleted. Our study underscores the critical need to precisely understand wt-HTT role in neuronal health. It also emphasizes the potential risks of excessive wt-HTT loss associated with non-selective therapeutic approaches targeting both wt- and mut-HTT isoforms in HD patients.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Corteza Cerebral
/
Células Madre Pluripotentes Inducidas
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Proteína Huntingtina
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Red Nerviosa
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article