Rapid Alpha-Synuclein Toxicity in a Neural Cell Model and Its Rescue by a Stearoyl-CoA Desaturase Inhibitor

Int J Mol Sci. 2020 Jul 22;21(15):5193. doi: 10.3390/ijms21155193.


Genetic and biochemical evidence attributes neuronal loss in Parkinson's disease (PD) and related brain diseases to dyshomeostasis of the 14 kDa protein α-synuclein (αS). There is no consensus on how αS exerts toxicity. Explanations range from disturbed vesicle biology to proteotoxicity caused by fibrillar aggregates. To probe these mechanisms further, robust cellular toxicity models are needed, but their availability is limited. We previously reported that a shift from dynamic multimers to monomers is an early event in αS dyshomeostasis, as caused by familial PD (fPD)-linked mutants such as E46K. Excess monomers accumulate in round, lipid-rich inclusions. Engineered αS '3K' (E35K+E46K+E61K) amplifies E46K, causing a PD-like, L-DOPA-responsive motor phenotype in transgenic mice. Here, we present a cellular model of αS neurotoxicity after transducing human neuroblastoma cells to express yellow fluorescent protein (YFP)-tagged αS 3K in a doxycycline-dependent manner. αS-3K::YFP induction causes pronounced growth defects that accord with cell death. We tested candidate compounds for their ability to restore growth, and stearoyl-CoA desaturase (SCD) inhibitors emerged as a molecule class with growth-restoring capacity, but the therapeutic window varied among compounds. The SCD inhibitor MF-438 fully restored growth while exerting no apparent cytotoxicity. Our αS bioassay will be useful for elucidating compound mechanisms, for pharmacokinetic studies, and for compound/genetic screens.

Keywords: Lewy body dementia; Parkinson’s disease; alpha-synuclein; cellular assay; neurotoxicity; protein misfolding; stearoyl-CoA desaturase.

MeSH terms

  • Bacterial Proteins
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Humans
  • Lewy Body Disease / drug therapy
  • Lewy Body Disease / metabolism
  • Luminescent Proteins
  • Mutation
  • Neuroblastoma / drug therapy
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Parkinson Disease / drug therapy
  • Parkinson Disease / metabolism
  • Pyridazines / pharmacology*
  • Stearoyl-CoA Desaturase / antagonists & inhibitors*
  • Stearoyl-CoA Desaturase / metabolism
  • Thiadiazoles / pharmacology*
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / toxicity*


  • Bacterial Proteins
  • Luminescent Proteins
  • MF 438
  • Pyridazines
  • Thiadiazoles
  • alpha-Synuclein
  • yellow fluorescent protein, Bacteria
  • Stearoyl-CoA Desaturase