Are alpha-synuclein fragments novel substrates of glutaminyl cyclase?

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The enzyme glutaminyl cyclase (QC) was demonstrated to be a prerequisite for the generation of highly neurotoxic Abeta peptide variants in brains of Alzheimer’s disease patients. Such pGlu- Abeta peptides are more resistant to degradation, display a high tendency to aggregate and can co-aggregate unmodified Abeta peptides. Thus, neurons which express QC are thought to represent vulnerable neuronal populations. The proposed research programme is based on our discovery of significant QC expression by substantia nigra neurons of men and mice and of the formation of a pGlu-α-synuclein fragment by QC. Therefore, we would like to address the following questions: (i) Is the concentration and/or activity of QC increased in brain of Parkinson’s disease patients? (ii) Are different α-synuclein fragments QC substrates? (iii) What are the aggregation characteristics of such pGlu-α-synuclein peptides? (iv) Are these pGlu-α-synuclein peptides present in brains of Parkinson’s disease patients? (v) Are the concentrations of pGlu-α-synuclein peptides affected by QC overexpression or knock-out in mouse brain? Answering these questions will help to elucidate novel pathological mechanisms underlying Parkinson’s disease and to discover yet unknown factors contributing to dopaminergic neuronal degeneration.