Mahmood, F., Fu, S., Cooke, J., Wilson, S.W., Cooper, J.D., and Russell, C. (2013) A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation. Brain : a journal of neurology. 136(Pt 5):1488-507.
Tripeptidyl peptidase 1 (TPP1) deficiency causes CLN2 disease, late infantile (or classic late infantile neuronal ceroid lipofuscinosis),
a paediatric neurodegenerative disease of autosomal recessive inheritance. Patients suffer from blindness, ataxia, epilepsy
and cognitive defects, with MRI indicating widespread brain atrophy, and profound neuron loss is evident within the retina
and brain. Currently there are no effective therapies for this disease, which causes premature death in adolescence. Zebrafish
have been successfully used to model a range of neurological and behavioural abnormalities. The aim of this study was to characterize
the pathological and functional consequences of Tpp1 deficiency in zebrafish and to correlate these with human CLN2 disease,
thereby providing a platform for drug discovery. Our data show that homozygous tpp1sa0011 mutant (tpp1sa0011/) zebrafish display a severe, progressive, early onset neurodegenerative phenotype, characterized by a significantly small
retina, a small head and curved body. The mutant zebrafish have significantly reduced median survival with death occurring
5 days post-fertilization. As in human patients with CLN2 disease, mutant zebrafish display storage of subunit c of mitochondrial
ATP-synthase, hypertrophic lysosomes as well as localized apoptotic cell death in the retina, optic tectum and cerebellum.
Further neuropathological phenotypes of these mutants provide novel insights into mechanisms of pathogenesis in CLN2 disease.
Secondary neurogenesis in the retina, optic tectum and cerebellum is impaired and axon tracts within the spinal cord, optic
nerve and the posterior commissure are disorganized, with the optic nerve failing to reach its target. This severe neurodegenerative
phenotype eventually results in functional motor impairment, but this is preceded by a phase of hyperactivity that is consistent
with seizures. Importantly, both of these locomotion phenotypes can be assayed in an automated manner suitable for high-throughput
studies. Our study provides proof-of-principle that tpp1sa0011/ mutants can utilize the advantages of zebrafish for understanding pathogenesis and drug discovery in CLN2 disease and other