PUBLICATION
CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease
- Authors
- Marchese, M., Bernardi, S., Vivarelli, R., Doccini, S., Santucci, L., Ogi, A., Licitra, R., Zang, J., Soliymani, R., Mero, S., Neuhauss, S.C., Ciarmoli, L., Signore, G., Lalowski, M.M., Santorelli, F.M.
- ID
- ZDB-PUB-250510-19
- Date
- 2025
- Source
- Molecular psychiatry 30: 4591-4604 (Journal)
- Registered Authors
- Santorelli, Filippo Maria, Zang, Jingjing
- Keywords
- none
- MeSH Terms
-
- Animals
- Biomarkers/metabolism
- Calcium/metabolism
- Disease Models, Animal
- Fibroblasts/metabolism
- Glucose*/metabolism
- Humans
- Lysosomal Membrane Proteins*/genetics
- Lysosomal Membrane Proteins*/metabolism
- Lysosomes/metabolism
- Membrane Proteins*/genetics
- Membrane Proteins*/metabolism
- Mutation/genetics
- Neuronal Ceroid-Lipofuscinoses*/genetics
- Neuronal Ceroid-Lipofuscinoses*/metabolism
- Phosphoglycerate Dehydrogenase*/genetics
- Phosphoglycerate Dehydrogenase*/metabolism
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 40346285 Full text @ Mol. Psychiatry
Citation
Marchese, M., Bernardi, S., Vivarelli, R., Doccini, S., Santucci, L., Ogi, A., Licitra, R., Zang, J., Soliymani, R., Mero, S., Neuhauss, S.C., Ciarmoli, L., Signore, G., Lalowski, M.M., Santorelli, F.M. (2025) CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease. Molecular psychiatry. 30:4591-4604.
Abstract
CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in the CLN5 gene encoding the lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and lysosomal function. Limited knowledge of cellular mechanisms and unclear drug targets hinder translating this to children's treatment, which remains symptomatic. We developed and characterized a new cln5 knock-out zebrafish model that replicates key features and molecular signatures of the human disease. Loss of Cln5 function in vivo altered axonal growth of retinal ON-bipolar cells and disrupted calcium homeostasis in the cerebellum, revealing new disease features. Additionally, multi-omic analyses at different developmental stages revealed an impaired glucose metabolism as an original finding in NCL. A novel biomarker, PHGDH, was validated in zebrafish and human skin fibroblasts harboring pathogenic variants in CLN5, and in CLN7. We also tested metformin which improved the expression of PHGDH in patient-derived cells, and rescued zebrafish behavior. This work demonstrates the profound metabolic impact of CLN5 dysfunction, offering a promising avenue toward targeted therapies for juvenile dementia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping