Abstract
The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive neurodegenerative disorders in children characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. Patients with mutations in CLN1 primarily manifest with infantile NCL (INCL or Haltia-Santavuori disease), which is second only to congenital NCL for its age of onset and devastating progression. CLN1 encodes a lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1). Nonsense mutations in CLN1 account for 52.3% of all disease causing alleles in infantile NCL, the most common of which worldwide is the p.R151X mutation. Previously, we have shown how nonsense-mediated decay is involved in the degradation of CLN1 mRNA transcripts containing the p.R151X mutation in human lymphoblast cell lines. We have also shown how the read-through drugs gentamicin and ataluren (PTC124) increase CLN1 (PPT1) enzyme activity. Here, we provide the initial characterization of the novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis that we have generated. This nonsense mutation model recapitulates the molecular, histological and behavioral phenotypes of the human disease. Cln1(R151X) mice showed a significant decrease in Cln1 mRNA level and PPT1 enzyme activity, accumulation of autofluorescent storage material, astrocytosis and microglial activation in the brain. Behavioral characterization of Cln1(R151X) mice at 3 and 5 months of age revealed significant motor deficits as measured by the vertical pole and rotarod tests. We also show how the read-through compound ataluren (PTC124) increases PPT1 enzyme activity and protein level in Cln1(R151X) mice in a proof-of-principle study.