Elevated tripeptidyl-peptidase 1 corrects multiple disease phenotypes in a mouse model of juvenile neuronal ceroid lipofuscinosis

Oct 6, 2025Molecular therapy. Methods & clinical development

Higher levels of tripeptidyl-peptidase 1 improve multiple symptoms in a mouse model of juvenile neuronal ceroid lipofuscinosis

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Abstract

Constitutively elevated TPP1 prevents SCMAS storage in a mouse model of juvenile neuronal ceroid lipofuscinosis.

Elevated expression of TPP1 is associated with reduced SCMAS accumulation in JNCL.
TPP1 overexpression leads to significant correction of neuroinflammation in the mouse model.
A reduction in elevated plasma biomarkers of neurodegeneration is observed with TPP1 augmentation.
Brain mass loss typically associated with aging in JNCL is significantly reduced by TPP1 overexpression.
These findings suggest that increasing TPP1 levels may provide a potential therapeutic approach for JNCL and similar lysosomal diseases.

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Juvenile neuronal ceroid lipofuscinosis (JNCL) is a neurodegenerative lysosomal storage disease caused by the loss of the endolysosomal transmembrane protein, CLN3. The main protein component of lysosomal storage material in JNCL is subunit c of mitochondrial ATP synthase (SCMAS), which is normally degraded within the lysosome by tripeptidyl-peptidase 1 (TPP1) during mitophagy. Previous studies have shown that TPP1 expression is elevated in JNCL, a potential compensatory response, while reduced levels of TPP1 exacerbate disease in a JNCL mouse model. These observations suggest a role for TPP1 in JNCL pathogenesis, and it is possible that lysosomal perturbations from the loss of CLN3 in JNCL could reduce the ability of TPP1 to degrade SCMAS. To test this hypothesis, we introduced a transgene that overexpresses TPP1 in a mouse model of JNCL and find that constitutively elevated TPP1 prevents SCMAS storage. This is associated with correction or significant reduction of other phenotypes of disease including neuroinflammation, an elevated plasma biomarker of neurodegeneration, and a disease-associated loss of brain mass with aging. From a clinical perspective, these results suggest that TPP1 augmentation could be a viable therapeutic strategy for JNCL and other lysosomal diseases that accumulate SCMAS where addressing the primary defect may be difficult or impossible.

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Elevated tripeptidyl-peptidase 1 corrects multiple disease phenotypes in a mouse model of juvenile neuronal ceroid lipofuscinosis

Abstract

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