Tripeptidyl-peptidase 1

Tripeptidyl-peptidase 1 (TPP1) is a lysosomal serine protease that catalyzes tripeptidyl-peptidase I activity, cleaving tripeptides from substrates with unsubstituted N-termini (UniProt: O14773). It functions as a non-specific lysosomal peptidase, processing breakdown products generated by other lysosomal proteinases. The protein is 563 amino acids in length.

TPP1 is expressed in neuronal tissues and has been associated with neurodegenerative lysosomal storage diseases. Biallelic mutations in TPP1 cause ceroid lipofuscinosis, neuronal, 2 (CLN2; MIM 204500), a progressive neurodegenerative disorder characterized by lysosomal accumulation of autofluorescent lipopigment, seizures, dementia, and visual loss (UniProt: O14773). The gene is also implicated in spinocerebellar ataxia, autosomal recessive, 7 (SCAR7; MIM 609270).

In Alzheimer's disease, TPP1 is upregulated in post-mortem AD brain relative to age-matched controls, with a mean log2 fold-change of 0.38 across analyzed subcellular fractions (Chaparral AD proteomics). This elevation may reflect compensatory lysosomal protease activity or altered proteolytic processing in the context of amyloid and tau pathology characteristic of AD.