Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Erik S. Musiek, Miranda Lim, Guangrui Yang, Adam Q. Bauer, Laura Qi, Yool Lee, Jee Hoon Roh, Xilma Ortiz-Gonzalez, Joshua T. Dearborn, Joseph P. Culver, Erik D. Herzog, John B. Hogenesch, David F. Wozniak, Krikor Dikranian, Benoit I. Giasson, David R. Weaver, David M. Holtzman, Garret A. FitzGerald

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Original languageEnglish (US)
Pages (from-to)5389-5400
Number of pages12
JournalJournal of Clinical Investigation
Volume123
Issue number12
DOIs
StatePublished - Dec 2 2013
Externally publishedYes

Fingerprint

Circadian Clocks
Oxidation-Reduction
Homeostasis
Genes
Brain
Proteins
Aryl Hydrocarbon Receptor Nuclear Translocator
Corpus Striatum
Presynaptic Terminals
Neuroglia
Biochemistry
Hippocampus
Sleep
Neurons
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Musiek, E. S., Lim, M., Yang, G., Bauer, A. Q., Qi, L., Lee, Y., ... FitzGerald, G. A. (2013). Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. Journal of Clinical Investigation, 123(12), 5389-5400. https://doi.org/10.1172/JCI70317

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. / Musiek, Erik S.; Lim, Miranda; Yang, Guangrui; Bauer, Adam Q.; Qi, Laura; Lee, Yool; Roh, Jee Hoon; Ortiz-Gonzalez, Xilma; Dearborn, Joshua T.; Culver, Joseph P.; Herzog, Erik D.; Hogenesch, John B.; Wozniak, David F.; Dikranian, Krikor; Giasson, Benoit I.; Weaver, David R.; Holtzman, David M.; FitzGerald, Garret A.

In: Journal of Clinical Investigation, Vol. 123, No. 12, 02.12.2013, p. 5389-5400.

Research output: Contribution to journalArticle

Musiek, ES, Lim, M, Yang, G, Bauer, AQ, Qi, L, Lee, Y, Roh, JH, Ortiz-Gonzalez, X, Dearborn, JT, Culver, JP, Herzog, ED, Hogenesch, JB, Wozniak, DF, Dikranian, K, Giasson, BI, Weaver, DR, Holtzman, DM & FitzGerald, GA 2013, 'Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration', Journal of Clinical Investigation, vol. 123, no. 12, pp. 5389-5400. https://doi.org/10.1172/JCI70317
Musiek, Erik S. ; Lim, Miranda ; Yang, Guangrui ; Bauer, Adam Q. ; Qi, Laura ; Lee, Yool ; Roh, Jee Hoon ; Ortiz-Gonzalez, Xilma ; Dearborn, Joshua T. ; Culver, Joseph P. ; Herzog, Erik D. ; Hogenesch, John B. ; Wozniak, David F. ; Dikranian, Krikor ; Giasson, Benoit I. ; Weaver, David R. ; Holtzman, David M. ; FitzGerald, Garret A. / Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 12. pp. 5389-5400.
@article{ed550789e3234239926d13f06a62d712,
title = "Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration",
abstract = "Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.",
author = "Musiek, {Erik S.} and Miranda Lim and Guangrui Yang and Bauer, {Adam Q.} and Laura Qi and Yool Lee and Roh, {Jee Hoon} and Xilma Ortiz-Gonzalez and Dearborn, {Joshua T.} and Culver, {Joseph P.} and Herzog, {Erik D.} and Hogenesch, {John B.} and Wozniak, {David F.} and Krikor Dikranian and Giasson, {Benoit I.} and Weaver, {David R.} and Holtzman, {David M.} and FitzGerald, {Garret A.}",
year = "2013",
month = "12",
day = "2",
doi = "10.1172/JCI70317",
language = "English (US)",
volume = "123",
pages = "5389--5400",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",

}

TY - JOUR

T1 - Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

AU - Musiek, Erik S.

AU - Lim, Miranda

AU - Yang, Guangrui

AU - Bauer, Adam Q.

AU - Qi, Laura

AU - Lee, Yool

AU - Roh, Jee Hoon

AU - Ortiz-Gonzalez, Xilma

AU - Dearborn, Joshua T.

AU - Culver, Joseph P.

AU - Herzog, Erik D.

AU - Hogenesch, John B.

AU - Wozniak, David F.

AU - Dikranian, Krikor

AU - Giasson, Benoit I.

AU - Weaver, David R.

AU - Holtzman, David M.

AU - FitzGerald, Garret A.

PY - 2013/12/2

Y1 - 2013/12/2

N2 - Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

AB - Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

UR - http://www.scopus.com/inward/record.url?scp=84890015150&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890015150&partnerID=8YFLogxK

U2 - 10.1172/JCI70317

DO - 10.1172/JCI70317

M3 - Article

VL - 123

SP - 5389

EP - 5400

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 12

ER -