Refolding and polymerization pathways of neuroserpin

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Neuroserpin mutations cause dementia by forming polymers in neurons.
• Polymer formation is proposed to occur via conformational changes in folded neuroserpin.
• An alternative hypothesis suggests polymerization happens during protein folding.

Purpose of the Study:

• Investigate refolding and polymerization pathways of wild-type neuroserpin (WT) and pathogenic mutants (S49P, H338R).
• Determine if polymerization occurs during folding or from the folded state.
• Identify potential therapeutic targets for neuroserpinopathies.

Main Methods:

• Refolding assays of WT and mutant neuroserpin.
• Characterization of refolding intermediates (I(IN), I(R)).
• Polymerization studies of intermediates under physiological conditions.

Main Results:

• WT neuroserpin refolds via I(IN) and I(R) intermediates.
• Mutants S49P and H338R exhibit altered refolding rates and yields.
• The I(R) intermediate of mutants readily forms polymers similar to native protein polymers.

Conclusions:

• Neuroserpin mutants show a higher propensity for polymerization during folding.
• Polymerization likely originates from a folding intermediate (I(R)), not solely from the native protein.
• Targeting the polymerogenic folding intermediate I(R) may offer a novel therapeutic approach for serpinopathies.