Journal article
Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
The Journal of clinical investigation, Vol.123(12), pp.5389-5400
12/01/2013
PMID: 24270424
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.
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Details
- Title
- Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
- Creators
- Erik S. Musiek - Washington Univ, Sch Med, Dept Neurol, Hope Ctr Neurol Disorders, St Louis, MO 63110 USAMiranda M. Lim - Univ Penn, Div Sleep Med, Perelman Sch Med, Philadelphia, PA 19104 USAGuangrui Yang - University of PennsylvaniaAdam Q. Bauer - Washington University in St. LouisLaura Oi - Supreme Council Of HealthYool Lee - Washington State University, Biomedical Sciences, Department ofJee Hoon Roh - Washington University in St. LouisXilma Ortiz-Gonzalez - Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USAJoshua T. Dearborn - Washington University in St. LouisJoseph P. Culver - Washington University in St. LouisErik D. Herzog - Washington University in St. LouisJohn B. Hogenesch - Cincinnati Children's Hospital Medical CenterDavid F. Wozniak - Washington University in St. LouisKrikor Dikranian - Washington University in St. LouisBenoit I. Giasson - University of FloridaDavid R. Weaver - University of Massachusetts Chan Medical SchoolDavid M. Holtzman - Washington Univ, Sch Med, Dept Neurol, Hope Ctr Neurol Disorders, St Louis, MO 63110 USAGarret A. FitzGerald - University of Pennsylvania
- Publication Details
- The Journal of clinical investigation, Vol.123(12), pp.5389-5400
- Academic Unit
- Elson S. Floyd College of Medicine
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 12
- Grant note
- R01HL097800 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Ellison Medical Foundation Senior Scholar Award; Lawrence Ellison Foundation P50AG005681 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Cure Alzheimer's Fund K08NS079405; R25NS065745; HL097800; P01NS074969; P30NS057105; NS056125; P30 NS057105 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01NS056125 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) AAN Clinical Research Training Fellowship
- Identifiers
- 99901132535001842
- Language
- English
- Resource Type
- Journal article