PUBLICATION
Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model
- Authors
- Marchese, M., Bernardi, S., Ogi, A., Licitra, R., Silvi, G., Mero, S., Galatolo, D., Gammaldi, N., Doccini, S., Ratto, G.M., Rapposelli, S., Neuhauss, S.C.F., Zang, J., Rocchiccioli, S., Michelucci, E., Ceccherini, E., Santorelli, F.M.
- ID
- ZDB-PUB-240520-6
- Date
- 2024
- Source
- Neurobiology of disease 197: 106536 (Journal)
- Registered Authors
- Neuhauss, Stephan, Santorelli, Filippo Maria, Zang, Jingjing
- Keywords
- Autophagy, Drug screening, Neuronal ceroid lipofuscinosis 8, Zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Autophagy*/drug effects
- Autophagy*/physiology
- Disease Models, Animal*
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Neuronal Ceroid-Lipofuscinoses*/genetics
- Neuronal Ceroid-Lipofuscinoses*/pathology
- Phenotype*
- Trehalose/pharmacology
- Zebrafish*
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 38763444 Full text @ Neurobiol. Dis.
Citation
Marchese, M., Bernardi, S., Ogi, A., Licitra, R., Silvi, G., Mero, S., Galatolo, D., Gammaldi, N., Doccini, S., Ratto, G.M., Rapposelli, S., Neuhauss, S.C.F., Zang, J., Rocchiccioli, S., Michelucci, E., Ceccherini, E., Santorelli, F.M. (2024) Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model. Neurobiology of disease. 197:106536.
Abstract
CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been linked to autophagy and lipid metabolism, but much remains to be learned, and there are no therapies acting on the molecular signatures in this disorder. The present study aims to characterize the molecular pathways involved in CLN8 disease and, by pinpointing altered ones, to identify potential therapies. To bridge the gap between cell and mammalian models, we generated a new zebrafish model of CLN8 deficiency, which recapitulates the pathological features of the disease. We observed, for the first time, that CLN8 dysfunction impairs autophagy. Using autophagy modulators, we showed that trehalose and SG2 are able to attenuate the pathological phenotype in mutant larvae, confirming autophagy impairment as a secondary event in disease progression. Overall, our successful modeling of CLN8 defects in zebrafish highlights this novel in vivo model's strong potential as an instrument for exploring the role of CLN8 dysfunction in cellular pathways, with a view to identifying small molecules to treat this rare disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping