Download What is the Molecular Clock? Components of the Molecular Clock

Circadian Rhythm Dysfunction in Psychiatric
Disorders
What is the Molecular Clock?
Components of the Molecular Clock
The Molecular Clock Involves a Cycle of Feedback Inhibition
Virtually all living creatures have an internal molecular clock that synchronizes biological processes such
as sleep/wake cycles, metabolism, and body temperature. The molecular clock oscillates with a period of
approximately 24-hours; thus, these biologically processes are described as circadian rhythms. Although
the molecular clock is self-sustaining, it needs to be reset daily or else it will drift and be out of synch with
environmental cues and resources. Such environmental stimuli include light/dark cycles generated by the
movement of the Earth and food availability. There are various factors that can reset the clock, however,
light is the most powerful synchronizer. Light entering through the eye is translated via the
retinohypothalamic tract to the suprachiasmatic nucleus (SCN) within the hypothalamus. During periods
of darkness, the SCN induces release of melatonin from the pineal gland. Interestingly, melatonin can
then act on receptors in the SCN to reset the molecular clock (Fig. 1).
At the molecular level, the circadian clock consists of various proteins called transcription factors that work together
in a series of negative feedback loops. These transcription factors bind to DNA regions called promoters, which are
DNA sequences found near a gene. The binding of a transcription factor to a promoter may turn the gene on or off,
thereby controlling production of proteins. In some cases, a heterodimer complex, formed by two different proteins,
can act together to regulate transcription. Specifically, the transcription factors that make up the molecular clock
include:
Heterodimers of CLOCK and BMAL1 bind to the E box promoter regions that regulate transcription of
various proteins, including PER and CRY. As PER and CRY accumulate, they heterodimerize to form a
complex. Expression of the nuclear receptor, REV-ERBα, is also regulated by binding of the
BMAL/CLOCK complex to an upstream promoter called the ROR/REV-ERBα response element (RRE)
(Fig 2A). PER, CRY, and REV-ERBα each provide negative feedback regulation of their own
expression. PER and CRY form a complex that inhibits CLOCK/BMAL1-regulated transcription. When
REV-ERBα binds the RRE, expression of BMAL1 is blocked (Fig 1B). With expression of PER, CRY,
and REV-ERBα inhibited due to the lack of CLOCK/BMAL1, feedback inhibition is no longer an issue.
Additionally, ROR binding to the RRE, stimulates expression of BMAL1. Once present, BMAL1 can
heterodimerize with CLOCK to begin the cycle of expression and feedback inhibition again (Fig 2C).
Both ROR and REV-ERBα are nuclear receptors poised to respond to cues from the environment,
such as light and melatonin. Other elements of the molecular clock, acting as transcriptional regulators
at other genes, can set into motion circadian behaviors such as sleep and metabolism.
Given the sensitivity of the molecular clock to external and internal cues, it is not surprising that the
molecular clock may become desynchronized due to many different factors. Social or lifestyle factors,
such as shift work, can desynchronize the molecular clock. Mutations in the clock genes that comprise
the molecular clock can lead to aberrant regulation of the molecular clock. Impaired neurotransmission,
resulting in excessive or insufficient neurotransmitter concentrations can also lead to desynchronization
of the molecular clock. Just as the molecular clock is influenced by neurotransmitters, many of the
components of the molecular clock in turn regulate levels of neurotransmitters, including serotonin. A
malfunctioning clock may therefore lead to impaired neurotransmission. Conversely, impaired
neurotransmission may have consequences to the synchronization of the molecular clock. Whether a
broken molecular clock is cause or effect, many psychiatric disorders, including depression,
schizophrenia, and bipolar disorder are associated with disturbances to circadian rhythms.
Pharmacological treatment of psychiatric disorders often entails restoring balance to dysfunctional
neurotransmitter systems. However, optimal outcomes might be achieved by also addressing dysfunction
in the molecular clock.
CLOCK
Circadian locomotor output cycles kaput
BMAL1
Brain and muscle ARNT-like-1
PERIOD
Period
CRY
Cryptochrome
REV-ERBα
Transcribed from the opposite strand of the thyroid receptor α (erb) gene
ROR
Retinoic acid-related orphan receptor
A
B
Mutations in Clock Genes Linked to Mental Illness
Many psychiatric disorders are associated with sleep disturbances. It is therefore not surprising that
polymorphisms in the genes for BMAL,CLOCK, CRY, PER, and REV-ERBα have each been
associated with various psychiatric disorders, including bipolar disorder, depression, schizophrenia,
and seasonal affect disorder.
C
Clock genes associated with psychiatric disorders
Clock Gene
Suprachiasmatic nucleus (SCN)
Mansour et al, 2006;
Nievergelt et al, 2006.
Bipolar
Clock
(or its homolog, NPAS)
Benedetti et al, 2003;
Soria et al 2010.
E
melatonin
Pineal
Gland
Retinohypothalamic tract
Bmal
CLOCK
CRY
E
E
E box
promoter region
E
PER
E
E
Cry
Retinohypothalamic Tract
Per
Figure 1. The suprachiasmatic nucleus is the master clock.
Virtually all living creatures have an internal molecular clock that synchronizes biological processes such as sleep/wake cycles, metabolism,
and body temperature. The molecular clock involves a set of f eedback loops that oscillate with a circadian rhythm of approximately 24-hours.
Although the molecular clock is self -sustaining, it needs to be reset daily, using both internal and external cues, to prevent desynchronization.
Synchronization of the molecular clock may be done by light/dark cycles, food intake, and by a variety of compounds, including melatonin and
serotonin.
Artioli P, Lorenzi C, Pirovano A et al. Eur Neuropsychopharmacol 2007;17(9):587-94.
Benedetti F, Seretti A, Columbo C et al. Am J Genet B Neuropsychiatr Genet 2003;123B(1):23-6.
Johansson C, Willeit M, Smedh C et al. Neuropsychopharmacol 2003;28(4):734-9.
Kripke DF, Nievergelt CM, Joo E et al. J Circad Rhythms 2009;7:2.
Mansour HA, Wood J, Logue T et al. Genes Brain Behav 2006;5(2):150-7.
Meyer JH, Ginovart N, Boovariwala A et al. Arch Gen Psychiatry 2006;63:1209-16.
Nievergelt CM, Kripke DF, Barrett TB et al. Am J Med Genet B Neuropsychiatr Genet 2006;141B(3):234-41.
Orzel-Gryglewska J. Int J Occup Med Environ Health 2010;23(1):95-114.
Partonen T, Treutlein J, Alpman A et al. Ann Med 2007;39(3):229-38.
Severino G, Manchia M, Contu P et al. Bipolar Disord 2009;11(2):215-20.
Soria V, Martínez-Amorós E, Escaramis G et al. Neuropsychopharmacol 2010;35(6):1279-89.
Takao T, Tachikawa H, Kawanashi Y et al. Eur Neuropsychopharmacol 2007;17(4):273-6.
Wulff K, Gatti S, Wettstein JG et al. Nat Rev Neurosci 2010;11(8):589-99.
E
REV-ERB α
E
E
ROR
RRE
ROR/REV-ERBα
response element
RRE
RRE
Figure 2. Feedback Inhibition of Molecular Clock Genes
A series of negative f eedback loops underlies the circadian rhythm of biological f unctions. A) A heterodimer complex of CLOCK and BMAL1 binds to the E box
promoter region turning on expression of CRY and PER. The BMALl1/CLOCK complex also turns off further expression of BMAL1. B) A heterodimer complex of
PER and CRY prevents BMAL1/CLOCK -regulated expression of PER and CRY proteins whereas the transcription f actor ROR turns on expression of BMAL1. C)
The cycle repeats as BMAL1 and CLOCK proteins accumulate and again turn on transcription of PER and CRY.
References
Bipolar
BMAL1
Suprachiasmatic nucleus (SCN)
Disorder
Rev-erbα
Depression
Soria et al 2010
Schizophrenia
Takao et al, 2007
Seasonal Affect Disorder
Johansson et al, 2003;
Partonen et al, 2007.
Depression
Soria et al, 2010
Bipolar
Nievergelt et al, 2006;
Artioli et al, 2007;
Mansour et al, 2006.
Depression
Artioli et al, 2007
Schizophrenia
Mansour et al, 2006.
Seasonal Affect Disorder
Partonen et al, 2007.
Bipolar
Kripke et al 2009;
Severino et al, 2009.
Presented at the 2011 NEI Global Psychopharmacology Congress.