PUBLICATION
Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity
- Authors
- Ferlazzo, G.M., Gambetta, A.M., Amato, S., Cannizzaro, N., Angiolillo, S., Arboit, M., Diamante, L., Carbognin, E., Romani, P., La Torre, F., Galimberti, E., Pflug, F., Luoni, M., Giannelli, S., Pepe, G., Capocci, L., Di Pardo, A., Vanzani, P., Zennaro, L., Broccoli, V., Leeb, M., Moro, E., Maglione, V., Martello, G.
- ID
- ZDB-PUB-230706-45
- Date
- 2023
- Source
- Nature communications 14: 39623962 (Journal)
- Registered Authors
- Moro, Enrico
- Keywords
- none
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Humans
- Huntingtin Protein/genetics
- Huntingtin Protein/metabolism
- Huntington Disease*/metabolism
- Mice
- Neurodegenerative Diseases*/metabolism
- Neurons/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 37407555 Full text @ Nat. Commun.
Citation
Ferlazzo, G.M., Gambetta, A.M., Amato, S., Cannizzaro, N., Angiolillo, S., Arboit, M., Diamante, L., Carbognin, E., Romani, P., La Torre, F., Galimberti, E., Pflug, F., Luoni, M., Giannelli, S., Pepe, G., Capocci, L., Di Pardo, A., Vanzani, P., Zennaro, L., Broccoli, V., Leeb, M., Moro, E., Maglione, V., Martello, G. (2023) Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity. Nature communications. 14:39623962.
Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity. Among the identified suppressors, linked to HD-associated processes, we focus on Metal response element binding transcription factor 1 (Mtf1). Forced expression of Mtf1 counteracts cell death and oxidative stress caused by mHTT in mouse ESCs and in human neuronal precursor cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mHTT. In R6/2 mice, Mtf1 ablates motor defects and reduces mHTT aggregates and oxidative stress. Our screening strategy enables a quick in vitro identification of promising suppressor genes and their validation in vivo, and it can be applied to other monogenic diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping