Alpha-synuclein biology in Lewy body diseases

alpha-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called alpha-synucleinopathies, which are characterized by the presence of aggregated alpha-synuclein intracellularly. Primary alpha-synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, with alpha-synuclein also found secondarily in a number of other diseases, including Alzheimer's disease. Understanding how alpha-synuclein aggregates form in these different disorders is important for the understanding of its pathogenesis in Lewy body diseases. PD is the most prevalent of the alpha-synucleinopathies and much of the initial research on alpha-synuclein Lewy body pathology was based on PD but is also relevant to Lewy bodies in other diseases (dementia with Lewy bodies and Alzheimer's disease). Polymorphism and mutation studies of SNCA, the gene that encodes alpha-synuclein, provide much evidence for a causal link between alpha-synuclein and PD. Among the primary alpha-synucleinopathies, multiple system atrophy is unique in that alpha-synuclein deposition occurs in oligodendrocytes rather than neurons. It is unclear whether alpha-synuclein originates from oligodendrocytes or whether it is transmitted somehow from neurons. alpha-Synuclein exists as a natively unfolded monomer in the cytosol, but in the presence of lipid membranes it is thought to undergo a conformational change to a folded alpha-helical secondary structure that is prone to forming dimers and oligomers. Posttranslational modification of alpha-synuclein, such as phosphorylation, ubiquitination and nitration, has been widely implicated in alpha-synuclein aggregation process and neurotoxicity. Recent studies using animal and cell models, as well as autopsy studies of patients with neuron transplants, provided compelling evidence for prion-like propagation of alpha-synuclein. This observation has implications for therapeutic strategies, and much recent effort is focused on developing antibodies that target extracellular alpha-synuclein.