Tripeptidyl-peptidase 1 (TPP1) (TPP1)

Tripeptidyl-peptidase 1 (TPP1) is a lysosomal serine protease that functions as an exopeptidase, specifically cleaving tripeptides from the N-termini of proteins (UniProt Consortium, 2023). In the central nervous system, TPP1 is essential for the degradation of proteins within the lysosomal compartment, and its absence leads to the accumulation of autofluorescent storage material known as lipofuscin (Mole et al., 2019). This accumulation is particularly toxic to neurons, leading to the clinical manifestation of Neuronal Ceroid Lipofuscinosis Type 2 (CLN2), a fatal neurodegenerative disorder (Kollmann et al., 2013). The enzyme is synthesized as a zymogen and undergoes autocatalytic activation in the acidic environment of the lysosome. Therapeutic strategies for CLN2 focus on restoring TPP1 activity, most notably through the use of Cerliponase alfa, a recombinant human TPP1 administered via intraventricular injection (FDA, 2017). This treatment aims to bypass the blood-brain barrier to reach the affected CNS cells and reduce the burden of lysosomal storage material. Monitoring of TPP1 activity and genetic testing for CLN2 mutations are standard diagnostic and prognostic tools in clinical practice.

Other names

TPP-1CLN2GIG1Lysosomal pepstatin-insensitive proteaseLPICSerine protease 1

Enzyme replacement therapy (ERT) where a recombinant form of the human enzyme is administered via intraventricular infusion to restore proteolytic activity within the lysosomes of CNS cells (FDA, 2017).