alpha-Synuclein and Parkinson's Disease (PD)

Alpha-synuclein is an intrinsically unfolded protein involved in Parkinson's disease and several neurodegenerative diseases that are summarized as synucleinopathies. The SNCA gene, which encodes alpha-synuclein, was the first gene identified in inherited forms of PD, and subsequently turned out to be a major risk factor also for the common sporadic form of the disease (Krüger et al., 1998; Singleton et al., 2009), however its pathological function in PD is still not well understood. In neurons, alpha-synuclein is predominantly localized in presynaptic nerve terminals. Only recently subcellular localization of a fraction of alpha-synuclein to the mitochondria has been described. Here alpha-synuclein was functionally linked to mitochondrial dysfunction based on partial trans-location into mitochondria.

Both, mutant and - to a lesser extent - physiological alpha-synuclein are prone to form protofibrils which subsequently aggregate to cytoplasmic inclusions called Lewy bodies. These Lewy bodies are the characteristic pathological hallmark for idiopathic PD.

Alpha-synuclein has been subsequently suggested to play a fundamental role in synaptic transport, transmitter release and cytotoxicity due to pore formation in the cell membrane.

We try to elucidate molecular pathomechanisms related to alpha-synuclein over-expression in different cellular models using genetic complementation approaches and live cell imaging technique.

Project: Andreas Hummel