title: Nrf2 mitigates LRRK2- and α-synuclein-induced neurodegeneration by modulating proteostasis.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.
authors.forename: Gaia
authors.initials: G
authors.lastname: Skibinski
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.
authors.forename: Vicky
authors.initials: V
authors.lastname: Hwang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.|Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143.
authors.forename: Dale Michael
authors.initials: DM
authors.lastname: Ando
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.|Medical Scientist Training Program, University of California, San Francisco, CA 94143.|Program in Bioengineering, University of California, San Francisco, CA 94143.
authors.forename: Aaron
authors.identifier: 0000-0001-8940-1780
authors.initials: A
authors.lastname: Daub
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Lee
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.
authors.forename: Abinaya
authors.initials: A
authors.lastname: Ravisankar
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.
authors.forename: Sara
authors.initials: S
authors.lastname: Modan
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
authors.forename: Mariel M
authors.initials: MM
authors.lastname: Finucane
authors.affiliation: Department of Statistics, Penn State University, State College, PA 16802.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Shaby
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158; sfinkbeiner@gladstone.ucsf.edu.|The Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA 94158.|The Hellman Foundation Program in Alzheimer's Disease Research, San Francisco, CA 94158.|Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143.|Department of Neurology, University of California, San Francisco, CA 94143.|Department of Physiology, University of California, San Francisco, CA 94143.|Graduate Programs in Neuroscience, University of California, San Francisco, CA 94143.
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D002479:Inclusion Bodies; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D061251:Primary Cell Culture; D066263:Protein Aggregation, Pathological; D000074702:Proteostasis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D059010:Single-Cell Analysis; D013997:Time Factors; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity
chemical_list: D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009419:Nerve Tissue Proteins; C495637:Nfe2l2 protein, rat; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; C018855:2-tert-butylhydroquinone; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: LRRK2; Nrf2; Parkinson’s disease; proteostasis; α-synuclein