An increasing number of human disorders are recognised to result from the aggregation and tissue deposition of misfolded proteins. This group of diseases has been termed the conformational disorders and comprises such diseases as Alzheimer’s, Huntington’s and Parkinson’s disease as well as the amyloidoses and the serpinopathies. The serpinopathies are characterized by the polymerisation and tissue deposition of mutants of members of the serine protease inhibitor or serpin superfamily of proteins. One of the most striking serpinopathies is familial encephalopathy with neuroserpin inclusion bodies (FENIB) that is caused by one of six naturally occurring point mutations in the neuroserpin gene. Mutant neuroserpin forms ordered polymers that accumulate within the endoplasmic reticulum of neurons, resulting in progressive dementia, with the age of onset of disease being inversely proportional to the rate of polymer formation in vitro and the number of intra-cerebral inclusions. This study will use an anti-polymer monoclonal antibody to (i) define the structure of the pathological neuroserpin polymer and its time-dependent appearance in the ER and (ii) as the basis for an intrabody strategy to prevent the inclusions associated with disease. First, regions of neuroserpin that are exposed upon transition from monomer to polymer will be analyzed by epitope mapping using differential chemical modification and crystallization aided by an antibody-engineered construct. Second, the ability of this anti-polymer monoclonal antibody to prevent pathogenic polymer formation and to impact their intracellular localization pattern will be assessed by co-expression with different neuroserpin mutants in cell and fly models of disease. The protective efficacy in vivo will be addressed by analyzing the locomotor phenotype in flies. If successful, an intracellular antibody based approach may be used to treat the serpinopathies and other ‘gain of function’ conformational diseases.
Field of science
- /natural sciences/chemical sciences/polymer science
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
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Funding SchemeMC-IEF - Intra-European Fellowships (IEF)