A loss in cellular protein partners promotes α-synuclein aggregation in cells resulting from oxidative stress.

ABSTRACT

There is a consensus that oxidative stress promotes neurodegeneration and may be linked to plaque formation. α-Synuclein is the main component of neurodegenerative plaques. We have found that α-synuclein binds strongly to the enzyme phospholipase Cß1 (PLCß1) in vitro and in cells affecting both its G protein activation and its degradation. Because PLCß1 binds to α-synuclein in cells, we tested whether decreasing its level would promote α-synuclein aggregation and whether overproducing PLCß1 would inhibit aggregation. By imaging fluorescent α-synuclein in living HEK293, PC12, and SK-H-SH cells, we find that α-synuclein aggregation is directly related to the level of PLCß1. Importantly, we found that oxidative stress does not affect the cellular levels of α-synuclein but results in the down-regulation of PLCß1 thereby promoting α-synuclein aggregation. A peptide that mimics part of the α-synuclein binding site to PLCß prevents aggregation. Our studies indicate that PLCß1 can reduce cell damage under oxidative stress and offers a potential site that might be exploited to prevent α-synuclein aggregation.