PUBLICATION
CLN3 deficiency leads to neurological and metabolic perturbations during early development
- Authors
- Heins-Marroquin, U., Singh, R.R., Perathoner, S., Gavotto, F., Merino Ruiz, C., Patraskaki, M., Gomez-Giro, G., Kleine Borgmann, F., Meyer, M., Carpentier, A., Warmoes, M.O., Jäger, C., Mittelbronn, M., Schwamborn, J.C., Cordero-Maldonado, M.L., Crawford, A.D., Schymanski, E.L., Linster, C.L.
- ID
- ZDB-PUB-240110-18
- Date
- 2024
- Source
- Life science alliance 7(3): (Journal)
- Registered Authors
- Cordero-Maldonado, Maria Lorena, Heins-Marroquin, Ursula, Linster, Carole
- Keywords
- none
- MeSH Terms
-
- Animals
- Cholesterol Esters
- Humans
- Induced Pluripotent Stem Cells*
- Membrane Glycoproteins/genetics
- Metabolomics
- Molecular Chaperones
- Neuronal Ceroid-Lipofuscinoses*/genetics
- Zebrafish/genetics
- PubMed
- 38195117 Full text @ Life Sci Alliance
Citation
Heins-Marroquin, U., Singh, R.R., Perathoner, S., Gavotto, F., Merino Ruiz, C., Patraskaki, M., Gomez-Giro, G., Kleine Borgmann, F., Meyer, M., Carpentier, A., Warmoes, M.O., Jäger, C., Mittelbronn, M., Schwamborn, J.C., Cordero-Maldonado, M.L., Crawford, A.D., Schymanski, E.L., Linster, C.L. (2024) CLN3 deficiency leads to neurological and metabolic perturbations during early development. Life science alliance. 7(3):.
Abstract
Juvenile neuronal ceroid lipofuscinosis (or Batten disease) is an autosomal recessive, rare neurodegenerative disorder that affects mainly children above the age of 5 yr and is most commonly caused by mutations in the highly conserved CLN3 gene. Here, we generated cln3 morphants and stable mutant lines in zebrafish. Although neither morphant nor mutant cln3 larvae showed any obvious developmental or morphological defects, behavioral phenotyping of the mutant larvae revealed hyposensitivity to abrupt light changes and hypersensitivity to pro-convulsive drugs. Importantly, in-depth metabolomics and lipidomics analyses revealed significant accumulation of several glycerophosphodiesters (GPDs) and cholesteryl esters, and a global decrease in bis(monoacylglycero)phosphate species, two of which (GPDs and bis(monoacylglycero)phosphates) were previously proposed as potential biomarkers for CLN3 disease based on independent studies in other organisms. We could also demonstrate GPD accumulation in human-induced pluripotent stem cell-derived cerebral organoids carrying a pathogenic variant for CLN3 Our models revealed that GPDs accumulate at very early stages of life in the absence of functional CLN3 and highlight glycerophosphoinositol and BMP as promising biomarker candidates for pre-symptomatic CLN3 disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping