Diverse Misfolding Mutant Digestive Enzymes Cause Chronic Pancreatitis Through Common Pathways

Area of Science:

• Gastroenterology
• Molecular Biology
• Genetics

Background:

• Protein misfolding and proteotoxicity are implicated in genetic chronic pancreatitis (CP).
• Mouse models with CPA1 N256K and PNLIP T221M variants mimic human CP phenotypes.
• These models provide a platform to investigate CP pathogenesis.

Purpose of the Study:

• To investigate the disease mechanisms underlying CP in mouse models with digestive enzyme variants.
• To compare the progression and severity of CP in CPA1 N256K and PNLIP T221M models.
• To identify potential therapeutic targets for genetic CP.

Main Methods:

• Histology, immunohistochemistry, immunoblotting, qPCR, TEM, and RNA-seq were used.
• Pancreatic pathological changes were characterized in mice aged 1 to 6 months.
• Gene expression and protein analysis were performed to understand cellular responses.

Main Results:

• Both homozygous models displayed hallmarks of CP, including acinar cell loss, inflammation, fibrosis, and fatty replacement.
• CP progression was slower in Cpa1 N256K mice and heterozygotes.
• Misfolded proteins induced endoplasmic reticulum stress, unfolded protein response, and apoptosis pathways.

Conclusions:

• Cpa1 N256K and Pnlip T221M mouse models develop CP through similar mechanisms with varying severity.
• These models are valuable for CP therapy development.
• Therapeutic strategies should focus on reducing misfolded digestive enzyme burden rather than targeting redundant cell death pathways.