TPP-I/CLN2 is a member of the sedolisin family of serine-carboxyl peptidases, and its loss causes a fatal neurodegenerative disease (late-infantile neuronal ceroid lipofuscinosis).

CLN2 orthologs are highly conserved and widely distributed across eukaryotes, including closely related but distinct enzymes present in fish such as zebrafish.

Homozygous tpp1(sa0011) mutant zebrafish are deficient in tripeptidyl peptidase 1 and display a severe, progressive, early onset neurodegenerative phenotype.

As in human CLN2 patients, the mutant zebrafish store subunit c of mitochondrial ATP-synthase and develop hypertrophic lysosomes with localized apoptotic cell death in the retina, optic tectum and cerebellum.

Secondary neurogenesis in the retina, optic tectum and cerebellum is impaired in tpp1 mutant zebrafish.

The neurodegenerative phenotype results in functional motor impairment preceded by a phase of seizure-like hyperactivity.

UniProt describes Tpp1 as a lysosomal serine protease with tripeptidyl-peptidase I activity that releases an N-terminal tripeptide from a polypeptide but also has endopeptidase activity (EC 3.4.14.9).

Tpp1 is localized to the lysosome and is activated by autocatalytic proteolytic processing from a precursor zymogen.

Zebrafish tpp1 encodes lysosomal tripeptidyl-peptidase 1 (EC 3.4.14.9), a sedolisin (S53)-family serine protease that acts mainly as an N-terminal exopeptidase releasing tripeptides, with limited endopeptidase activity.

The TPP1 catalytic triad is consistent with sedolisin-family enzymes, reported as Glu-Asp-Ser, distinguishing it from classical Ser-His-Asp serine proteases.

Zebrafish Tpp1 is predicted to be targeted to the lysosome after removal of a 19-aa signal peptide and is trafficked to lysosomes via the mannose-6-phosphate pathway.

Tpp1 activity in zebrafish embryos is measured as cleavage of the fluorogenic tripeptidyl substrate Arg-Ala-Phe-ACC at acidic pH (pH 4.0), consistent with a lysosomal enzyme, and is significantly reduced in tpp1(sa0011) mutants.

Loss of Tpp1 produces classic lysosomal storage phenotypes including enlarged/hypertrophic lysosomes and accumulation of subunit c of mitochondrial ATP synthase (SCMAS), positioning Tpp1 within lysosome-dependent proteostasis and degradative pathways.

Homozygous tpp1(sa0011) mutants show an early-onset, progressive neurodegenerative phenotype with defects in retina, optic tectum and cerebellum, increased apoptosis, sustained reduction in proliferation, seizure-like hyperactivity, and motor decline.