Levodopa (L-DOPA) attenuates endoplasmic reticulum stress response and cell death signaling through DRD2 in SH-SY5Y neuronal cells under α-synuclein-induced toxicity

Neuroscience. 2017 Sep 1;358:336-348. doi: 10.1016/j.neuroscience.2017.06.060. Epub 2017 Jul 4.


Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in dopaminergic neurons. α-Synuclein (α-syn), a major protein component of LBs, is known to regulate synaptic plasticity, with a crucial role in memory and motor function in the central nervous system. Levodopa (L-3,4-dihydroxyphenylalanine; also known as L-DOPA) is considered the most effective medication for controlling the symptoms of PD. However, it is unclear whether L-DOPA improves the neuropathology of PD. In the present study, we investigated the effect of L-DOPA on SH-SY5Y neuronal cells under α-syn-induced toxicity. We assessed the protein and mRNA levels of endoplasmic reticulum (ER) stress and cell death markers using western blot analysis and reverse transcription-PCR. Our data showed that L-DOPA could attenuate ER stress markers, including the levels of activating transcription factor 4 (ATF4), C/EBPhomologous protein expression (CHOP), immunoglobulin-heavy-chain-binding protein (BiP), sliced X-box-binding protein 1 (XBP-1), and reduce nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling through dopamine receptor D2 (DRD2) in SH-SY5Y neuronal cells under α-syn-induced toxicity. In conclusion, we suggest that L-DOPA may attenuate the neuropathology of PD by regulating signaling related to DRD2 in neuronal cells under α-syn-induced toxicity. Our study, therefore, indicates an additional role for L-DOPA in the treatment of PD.

Keywords: Parkinson’s disease; SH-SY5Y neuronal cells; dopamine receptor D2; endoplasmic reticulum stress; levodopa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Disks Large Homolog 4 Protein / genetics
  • Disks Large Homolog 4 Protein / metabolism
  • Dopamine Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum Stress / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Iron-Regulatory Proteins / genetics
  • Iron-Regulatory Proteins / metabolism
  • Levodopa / pharmacology*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neuroblastoma / pathology
  • Neurons / drug effects*
  • Neurons / metabolism
  • RNA, Messenger
  • Receptors, Dopamine D2 / metabolism*
  • Signal Transduction / drug effects*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / pharmacology
  • bcl-2-Associated X Protein / metabolism


  • DRD2 protein, human
  • Disks Large Homolog 4 Protein
  • Dopamine Agents
  • Iron-Regulatory Proteins
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Dopamine D2
  • alpha-Synuclein
  • bcl-2-Associated X Protein
  • Levodopa
  • CREB-Binding Protein