A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.
Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.
Division of Basic Biomedical Sciences. Sanford School of Medicine at the University of South Dakota, Vermillion, South Dakota, United States of America ; Children's Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America.
Jeremy P
JP
Morgan
Helen
H
Magee
Andrew
A
Wong
Tarah
T
Nelson
Bettina
B
Koch
Jonathan D
JD
Cooper
Jill M
JM
Weimer
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D007859:Learning Disabilities / Q000235:genetics / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D014786:Vision Disorders / Q000235:genetics / Q000503:physiopathology
C486722:Cln6 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins