TPP1 (tripeptidyl peptidase 1) serves dual critical functions in human cells: lysosomal protein degradation and telomere maintenance. As a lysosomal serine protease, TPP1 exhibits tripeptidyl-peptidase activity, generating tripeptides from breakdown products of lysosomal proteinases and requiring substrates with unsubstituted N-termini 1. In telomere biology, TPP1 forms part of the shelterin complex, specifically heterodimerizing with POT1 to protect chromosome 11 and recruit telomerase 2. Structural studies reveal that TPP1 creates a structured interface with telomerase components TERT-TEN and TRAP domains, stabilizing DNA and enhancing telomerase processivity 34. TPP1-POT1 binding suppresses ATR-dependent DNA damage responses and is essential for telomere length regulation 5. Disease relevance includes neuronal ceroid lipofuscinosis type 2 (CLN2) caused by TPP1 mutations, leading to progressive neurodegeneration 6. Additionally, TPP1 promoter mutations cooperate with TERT promoter mutations in melanoma to enhance telomere maintenance and cellular immortalization 7. Mendelian randomization studies implicate TPP1 in amyotrophic lateral sclerosis pathogenesis, highlighting its broader neurological significance 8.