The role of lipids in α-synuclein misfolding and neurotoxicity

J Biol Chem. 2019 Jun 7;294(23):9016-9028. doi: 10.1074/jbc.REV119.007500. Epub 2019 May 7.


The misfolding and aggregation of α-synuclein (αsyn) 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, αsyn acquires pathogenic properties, such as neurotoxicity, that can contribute to disease development. The mechanisms that produce αsyn 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 αsyn's pathogenicity is its ability to associate with lipids. This appears important not only to how αsyn 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 αsyn 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.

Keywords: Lewy body; Parkinson disease; alpha-synuclein; amyloid; lipid; mitochondrial function; neurodegeneration; neurodegenerative disease; neurotoxicity; protein misfolding; synucleinopathy.

Publication types

  • Review

MeSH terms

  • Central Nervous System / metabolism
  • Fatty Acids, Unsaturated / chemistry
  • Fatty Acids, Unsaturated / metabolism
  • Humans
  • Lipids / chemistry*
  • Protein Aggregation, Pathological
  • Proteostasis Deficiencies / metabolism
  • Proteostasis Deficiencies / pathology
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism*


  • Fatty Acids, Unsaturated
  • Lipids
  • alpha-Synuclein