A Murine Model of Variant Late Infantile Ceroid Lipofuscinosis Recapitulates Behavioral and Pathological Phenotypes of Human Disease

Jeremy P Morgan,Helen Magee,Andrew Wong,Bettina Koch,Jill M Weimer,Tarah Nelson,Jonathan D Cooper

doi:10.1371/journal.pone.0078694

Abstract

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 (Cln6nclf) mouse line to validate its utility for translational research. We demonstrate that this Cln6nclf 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 Cln6nclf mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

Highlights

The neuronal ceroid lipofuscinoses (NCLs) are a family of fatal lysosomal storage diseases composed of at least 10 disease variants (Reviewed in [1,2,3])
The most common mutation in CLN6, which leads to variant late infantile NCL (vLINCL), results from the insertion of an additional cytosine at base pair 307 in exon 4, leading to a frameshift and premature stop codon. vLINCL disease onset occurs between 18 months and eight years of age, with symptoms of motor delay, vision loss, dystharthia, and ataxia followed by premature death during the second decade of life [16,17]
The NCLs are a devastating family of genetic disorders which manifests in early childhood with vision loss, motor decline, seizures, and culminates in premature death (Reviewed in [7])

Summary

Introduction

The neuronal ceroid lipofuscinoses (NCLs) are a family of fatal lysosomal storage diseases composed of at least 10 disease variants (Reviewed in [1,2,3]) These diseases are classically characterized by accumulation of autofluorescent storage material within cells of the brain and other tissues and mutations in as many as 13 genes have been reported to cause NCLs (Reviewed in [3,4,5]; see http://www.ucl.ac.uk/ncl/mutation.shtml). Genetically distinct, this family of disorders shares overlapping disease symptomatology, including early onset visual deterioration, declining motor coordination, frequent seizures, mental deterioration, and premature death (Reviewed in [6,7]). The most common mutation in CLN6, which leads to vLINCL, results from the insertion of an additional cytosine at base pair 307 in exon 4, leading to a frameshift and premature stop codon. vLINCL disease onset occurs between 18 months and eight years of age, with symptoms of motor delay, vision loss, dystharthia, and ataxia followed by premature death during the second decade of life [16,17]

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Results

Conclusion