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

Gaia Skibinski, Vicky Hwang, Dale Michael Ando, Aaron Daub, Alicia K. Lee, Abinaya Ravisankar, Sara Modan, Mariel M. Finucane, Benjamin A. Shaby, Steven Finkbeiner

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1165-1170
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number5
DOIs
StatePublished - Jan 31 2017

All Science Journal Classification (ASJC) codes

  • General

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