Serine endopeptidase tripeptidyl peptidase II maintains lysosomal homeostasis to alleviate Parkinson’s disease pathogenesis

Parkinson's disease is neuropathologically characterized by the progressive loss of dopaminergic neurons and the pathological accumulation of α-synuclein. While these hallmarks are well established, the molecular drivers of this irreversible neurodegenerative process are not fully understood. Through an integrated multi-omics approach combining nascent protein mass spectrometry and bulk RNA sequencing of cellular and transgenic Parkinson's disease mouse models, we revealed suppressed serine endopeptidase activity during the early pathogenic stages of the disease. Subsequent functional analyses identified tripeptidyl peptidase II as the principal enzyme mediating serine endopeptidase activity, as demonstrated through a series of biochemical assays. Mechanistic investigations showed that tripeptidyl peptidase II deficiency impairs lysosomal function, prolongs the clearance of α-synuclein fibrillar seeds, and disrupts synaptic homeostasis in hippocampal neurons. Importantly, overexpression of tripeptidyl peptidase II effectively attenuated pathological α-synuclein aggregation and prevented the cell-to-cell propagation of α-synuclein pathology in wild-type mice injected with α-synuclein preformed fibrils. Our findings establish tripeptidyl peptidase II as a critical regulator of lysosome-mediated amyloidogenic seed degradation and reveal its neuroprotective role against α-synuclein-associated synucleinopathies.