Nrf2 mitigates LRRK2- and α-synuclein-induced neurodegeneration by modulating proteostasis

Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1165-1170. doi: 10.1073/pnas.1522872114. Epub 2016 Dec 27.


Mutations in leucine-rich repeat kinase 2 (LRRK2) and α-synuclein lead to Parkinson's disease (PD). Disruption of protein homeostasis is an emerging theme in PD pathogenesis, making mechanisms to reduce the accumulation of misfolded proteins an attractive therapeutic strategy. We determined if activating nuclear factor erythroid 2-related factor (Nrf2), a potential therapeutic target for neurodegeneration, could reduce PD-associated neuron toxicity by modulating the protein homeostasis network. Using a longitudinal imaging platform, we visualized the metabolism and location of mutant LRRK2 and α-synuclein in living neurons at the single-cell level. Nrf2 reduced PD-associated protein toxicity by a cell-autonomous mechanism that was time-dependent. Furthermore, Nrf2 activated distinct mechanisms to handle different misfolded proteins. Nrf2 decreased steady-state levels of α-synuclein in part by increasing α-synuclein degradation. In contrast, Nrf2 sequestered misfolded diffuse LRRK2 into more insoluble and homogeneous inclusion bodies. By identifying the stress response strategies activated by Nrf2, we also highlight endogenous coping responses that might be therapeutically bolstered to treat PD.

Keywords: LRRK2; Nrf2; Parkinson’s disease; proteostasis; α-synuclein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / cytology
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Hydroquinones / pharmacology
  • Inclusion Bodies
  • Induced Pluripotent Stem Cells / cytology
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / toxicity
  • NF-E2-Related Factor 2 / biosynthesis
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / physiology*
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Parkinson Disease / metabolism*
  • Primary Cell Culture
  • Protein Aggregation, Pathological
  • Proteostasis
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Single-Cell Analysis
  • Time Factors
  • alpha-Synuclein / antagonists & inhibitors*
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / toxicity


  • Hydroquinones
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nerve Tissue Proteins
  • Nfe2l2 protein, rat
  • Recombinant Fusion Proteins
  • alpha-Synuclein
  • 2-tert-butylhydroquinone
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2