Protein misfolding and the serpinopathies

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Serpins represent the largest superfamily of protease inhibitors, present across diverse life forms.
• They regulate protease activity through a unique conformational transition mechanism.
• This mechanism's complexity and involvement in vital biological processes predispose serpins to mutation-related diseases.

Purpose of the Study:

• To elucidate the common polymerization mechanism underlying various serpin-related diseases.
• To introduce a novel classification for these conditions based on shared molecular pathology.
• To highlight the correlation between molecular instability, polymer formation rate, and disease severity.

Main Methods:

• Comparative analysis of mutation-related diseases affecting serpins like alpha(1)-antitrypsin and neuroserpin.
• Investigation of polymerization processes in the endoplasmic reticulum and neurons.
• Correlation studies linking molecular instability and disease progression.

Main Results:

• Mutant serpins, such as alpha(1)-antitrypsin and neuroserpin, form ordered polymers leading to endoplasmic reticulum accumulation and diseases like cirrhosis and dementia (FENIB).
• A similar polymerization mechanism causes hepatic retention and plasma deficiency in antithrombin, C1 inhibitor, alpha(1)-antichymotrypsin, and heparin co-factor II.
• A direct correlation exists between molecular instability, polymer formation rate, and the clinical severity of these diseases.

Conclusions:

• The shared polymerization mechanism across multiple serpinopathies provides a unifying framework for understanding these diseases.
• These findings establish a novel class of diseases, termed 'serpinopathies', based on a common molecular pathogenesis.
• Understanding this mechanism is crucial for developing targeted therapies for serpinopathies.