SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

Quinti, Luisa; Casale, Malcolm; Moniot, S.; Pais, Teresa F.; Kanegan, Michael J. Van; Kaltenbach, Linda S.; Pallos, Judit; Lim, Ryan G.; Naidu, Sharadha Dayalan; Runne, Heike; Meisel, Lisa; Rauf, Nazifa Abdul; Leyfer, Dmitriy; Maxwell, Michelle; Saiah, Eddine; Landers, John E.; Lüthi-Carter, Ruth; Abagyan, Ruben; Dinkova‐Kostova, Albena T.; Steegborn, Clemens; Marsh, J. Lawrence; Lo, Donald C.; Thompson, Leslie M.; Kazantsev, Aleksey G.

doi:10.1016/j.chembiol.2016.05.015

Cited by 71 publications

(61 citation statements)

References 49 publications

(75 reference statements)

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“…However, growing evidence indicates that Nrf2 can act in neurons via a cell-autonomous manner, leading to transcriptional changes in not only oxidative stress-related genes but also those related to proteostasis and specific neuronal functions (45)(46)(47). Our work demonstrates that Nrf2 can act in a cell-autonomous manner to potently promote neuronal protein homeostasis and reduce neurodegeneration caused by α-synuclein and mutant LRRK2 expression.…”

Section: Discussionmentioning

confidence: 74%

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

Skibinski

Hwang

Ando

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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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.Nrf2 | Parkinson's disease | LRRK2 | α-synuclein | proteostasis

show abstract

Section: Discussionmentioning

confidence: 74%

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

Skibinski

Hwang

Ando

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

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“…However, neither overexpression of cytosolic Zn/Cu‐SOD or mitochondrial MnSOD, nor nutritional supplementation with α‐tocopherol and coenzyme Q10, has led to prolongation of the lifespan of Drosophila HD model flies. By contrast, activation of the Nrf2 pathway by SIRT2 inhibition and induction of NQO1 appears to be very promising and effective with respect to protecting oxidative damage in rodent and human HD models .…”

Section: Huntington's Diseasementioning

confidence: 98%

Role of mitochondrial ROS in the brain: from physiology to neurodegeneration

Angelova¹,

Abramov²

2018

FEBS Letters

549

350

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Edited by Wilhelm JustMitochondria are key cell organelles in that they are responsible for energy production and control many processes from signalling to cell death. The function of the mitochondrial electron transport chain is coupled with the production of reactive oxygen species (ROS) in the form of superoxide anion or hydrogen peroxide. As a result of the constant production of ROS, mitochondria are protected by highly efficient antioxidant systems. The rapidly changing levels of ROS in mitochondria, coupled with multiple essential cellular functions, make ROS apt for physiological signalling. Thus, mutations, environmental toxins and chronic ischaemic conditions could affect the mitochondrial redox balance and lead to the development of pathology. In long-living and non-mitotic cells such as neurons, oxidative stress induced by overproduction of mitochondrial ROS or impairment of the antioxidant defence results in a dysfunction of mitochondria and initiation of the cell death cascade. Mitochondrial ROS overproduction and changes in mitochondrial redox homeostasis have been shown to be involved in both a number of neurological conditions and a majority of neurodegenerative diseases. Here, we summarise the involvement of mitochondrial ROS in the mechanism of neuronal loss of major neurodegenerative disorders.

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“…The anti‐inflammatory properties of Nrf2 signaling are well established, and recent evidence suggests a mechanism of transcriptional repression of proinflammatory cytokines (TNF‐α, IL‐1, IL‐6, IL‐8, MCP‐1) in microglia, macrophages, monocytes, and astrocytes following Nrf2 activation . The Nrf2 activator sulforaphane increased Nrf2 DNA‐binding activity and upregulated Nrf2 target genes in RAW264.7 cells, BV2 microglia cells and primary mouse microglia, while reducing LPS‐induced interleukin IL‐1β, IL‐6, and inducible nitric oxide synthase (iNOS) . Furthermore, representatives of seven distinct chemical classes of Nrf2 activators show highly correlated upregulation of NQO1 – a prototypic Nrf2 target – and suppression of iNOS and COX‐2 expression in cell lines and primary mouse peritoneal macrophages .…”

Section: Role Of Nrf2 In Neuroinflammationmentioning

confidence: 99%

“…Dimethylfumarate is, however, of a relatively low potency and specificity. Other molecules with similar mechanism of action or with the ability to directly disrupt the Keap1/Nrf2 interaction are emerging as potential protective agents for the prevention and treatment of a broad range of currently incurable neurodegenerative diseases . Inhibition of Keap1 has also been shown to prevent neuronal toxicity in response to the AD‐initiating Aβ42 peptide, in correlation with Nrf2 activation .…”

Section: Nrf2‐dependent Amelioration Of Age‐dependent Neurological Phmentioning

confidence: 99%

The role of Nrf2 signaling in counteracting neurodegenerative diseases

2018

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The transcription factor Nrf2 (nuclear factor‐erythroid 2 p45‐related factor 2) functions at the interface of cellular redox and intermediary metabolism. Nrf2 target genes encode antioxidant enzymes, and proteins involved in xenobiotic detoxification, repair and removal of damaged proteins and organelles, inflammation, and mitochondrial bioenergetics. The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.

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SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models

Cited by 71 publications

References 49 publications

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

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

Role of mitochondrial ROS in the brain: from physiology to neurodegeneration

The role of Nrf2 signaling in counteracting neurodegenerative diseases

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