The role of lipids in α-synuclein misfolding and neurotoxicity

The misfolding and aggregation of -synuclein (syn) in the central nervous system is associated with a group of neurodegenerative disorders referred to as the synucleinopathies. In addition to being a pathological hallmark of disease, it is now well-established that upon misfolding, syn acquires pathogenic properties, such as neurotoxicity, that can contribute to disease development. The mechanisms that produce syn misfolding and the molecular events underlying the neuronal damage caused by these misfolded species are not well-defined. A consistent observation that may be relevant to syn's pathogenicity is its ability to associate with lipids. This appears important not only to how syn aggregates, but also to the mechanism by which the misfolded protein causes intracellular damage. This review discusses the current literature reporting a role of lipids in syn misfolding and neurotoxicity in various synucleinopathy disorders and provides an overview of current methods to assess protein misfolding and pathogenicity both in vitro and in vivo.