Protein aggregates

Lewy bodies are cytoplasmic inclusions of fibrillary protein aggregates, consisting of alpha-synuclein and other proteins. They are characteristically found in the brains of patients with Parkinson’s disease (PD) but also in a number of other conditions termed synucleinopathies (Dementia with Lewy bodies, Pure autonomic Failure, Multi System Atrophy). Protein aggregation can result from an increased tendency of misfolded protein to aggregate or from an impairment of protein degradation by the ubiquitin proteasome system. Mutations in the alpha-synuclein gene that increase its tendency to misfold and aggregate, and also mutations in genes involved in proteasomal protein degradation have been found to be responsible for inherited forms of PD. This suggests that protein aggregation may play an important role in the pathogenesis of PD in general. It remains unclear, however, whether full-blown Lewy bodies or oligomere precursors termed protofibrils are responsible for neurotoxicity.

We are currently using the MPTP model and genetically modified mice expressing mutant human A30P-alpha-synuclein, the latter which causes autosomal dominant PD in humans. By expressing proteins favouring or inhibiting protein aggregation through viral gene transfer, we are investigating the selective vulnerability of certain cell types and that the connections between oxidative stress and protein aggregation, and between protein aggregation and neurotoxicity. At the same time we are exploring pharmacological and genetic strategies for neuroprotective therapy.