Impact of proteolytic cleavage of alpha-synuclein by calpain in the pathogenesis of Parkinson’s Disease (PD) in a transgenic animal model

Coordinator:		Prof.Dr. Olaf Riess
Institution:		Institutfür Medizinische Genetik und Angewandte Genomik, Universitätsklinikum Tübingen
Homepage:		http://www.uni-tuebingen.de/uni/thk

Alpha-synuclein is a small protein in the brain and involved in the pathogenesis of synucleinopathies like Parkinson and Multiple System Atrophy (MSA). Thereby it comes to intracellular protein deposits of misfolded alpha-synuclein (aSyn). The mechanism why the protein is changing the conformation, subsequently accumulates and is getting toxic is still not clarified.   Calpains are calcium-dependent proteases and have their function in several essential neuronal functions. Changes in the calcium homeostasis lead to a permanent and pathological activation of calpain in several neurodegenerative diseases.

Here we investigated whether calpains may cleave alpha-synuclein in vivo. Calpain-cleaved alpha-synuclein fragments, which are accumulating and getting toxic for the cell, were already detected in PD patients post mortem. So far only one natural existing calpain inhibitor suppressing the activation of calpain is known: calpastatin.

In this study we studied the role of calpain in the pathogenesis of PD. We crossbreed one well-known mouse models for Parkinson’s disease overexpressing human synuclein (aSyn) with the two following mice models:
1.    calpastatin inactivation, which results in a permanent (pathological) calpain activation
2.    calpastatin overexpression resulting in a nearly complete inactivation of calpain

We were able to show that through the inactivation of calpain the fragments of aSyn were not detectable anymore and that the aggregation load was significantly reduced.

To sum up, we conclude that, beside other proteases, calpains play an important role in the pathogenesis of PD and represent a possible target for therapeutically studies in the future.