Journal Article

A tailored mouse model of CLN2 disease: A nonsense mutant for testing personalized therapies

Beraldi, Rosanna, Geraets, Ryan D., Pearce, David A., Kovacs, Attila D., Parker, Camille M., Weimer, Jill M., Langin, Logan M., Cain, Jacob T.

2017

Overview

The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. The NCLs result in premature death due to the absence of curative therapies. Nevertheless, preclinical and clinical trials exist for various therapies. However, the genotypes of NCL animal models determine which therapeutic approaches can be assessed. Mutations of the CLN2 gene encoding a soluble lysosomal enzyme, tripeptidyl peptidase 1 (TPP1), cause late infantile NCL/CLN2 disease. The genotype of the original mouse model of CLN2 disease, Cln2-/-, excludes mutation guided therapies like antisense oligonucleotides and nonsense suppression. Therefore, the purpose of this study was to develop a model of CLN2 disease that allows for the assessment of all therapeutic approaches. Nonsense mutations in CLN2 disease are frequent, the most common being CLN2R208X. Thus, we created a mouse model that carries a mutation equivalent to the human p.R208X mutation. Molecular assessment of Cln2R207X/R207X tissues determined significant reduction in Cln2 transcript abundance and TPP1 enzyme activity. This reduction leads to the development of neurological impairment (e.g. tremors) and neuropathology (e.g. astrocytosis). Collectively, these assessments indicate that the Cln2R207X/R207X mouse is a valid CLN2 disease model which can be used for the preclinical evaluation of all therapeutic approaches including mutation guided therapies.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Age / Amino acid sequence / Aminoglycoside antibiotics / Aminoglycosides / Aminopeptidases - genetics / Animal models / Animals / Antisense oligonucleotides / Assaying / Attenuation / Behavior, Animal / Biology and Life Sciences / Brain / Brain - pathology / Brain research / Care and treatment / Central nervous system / Cerebellum / Chains (polymeric) / Children / Clinical trials / CLN2 protein / Codon, Nonsense - genetics / Codon, Nonsense - physiology / Cognitive ability / Colonies / Cortex (motor) / Death / Decay / Diagnosis / Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics / Disease / Disease Models, Animal / Drugs / Enzymatic activity / Enzyme activity / Enzymes / Epilepsy / Falls / Gene mutation / Genes / Genetic aspects / Genomics / Genotypes / Gliosis - pathology / Hippocampus / Immune system / In vivo methods and tests / LSD / Lysergic acid diethylamide / Male / Medical research / Medicine / Membrane proteins / Mice / Mice, Knockout / Mortality / Mucopolysaccharides / Mutation / Nervous system / Neurodegeneration / Neurodegenerative diseases / Neuronal ceroid lipofuscinosis / Neuronal Ceroid-Lipofuscinoses - genetics / Neuronal Ceroid-Lipofuscinoses - pathology / Neuronal Ceroid-Lipofuscinoses - therapy / Neuronal-glial interactions / Nucleic acids / Oligonucleotides / Pathology / Physiological effects / Polymerase chain reaction / Proteins / Protocol (computers) / Reduction / Research and Analysis Methods / Serine Proteases - genetics / Stem cells / Stop codon / Storage / Substrates / Transcription / Tripeptidyl-Peptidase 1