Loss Of Circadian Genes Results In Epilepsy 6/7/2004
From: JWissmille (jwissmille_at_aol.com)
Date: 06/23/04
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Date: 23 Jun 2004 01:10:50 GMT
http://news.biocompare.com/newsstory.asp?id=40529
Loss Of Circadian Genes Results In Epilepsy
6/7/2004
Source: Cold Spring Harbor Laboratory
A meticulous series of experiments – and the fortuitous use of a vacuum
cleaner – lead to breakthrough new insight on the genetic basis of
epilepsy.
Circadian rhythms -- the normal ups and downs of body rhythms – help
organize physiological processes into a 24 hour cycle, affecting everythiing
from body temperature, hormone levels and heart rate, to pain thresholds.
Scientists have now discovered that the combined deletion of three circadian
genes, encoding the PAR bZip transcription factor protein family, results in
accelerated aging and severe epilepsy in mice. Owing to the roughly 95%
identity of PAR bZip proteins between mice and humans, it is anticipated that
PAR bZip mutations may also underlie some forms of human epilepsy.
A copy of this important new study is being released in advance of its June
15th publication date by the journal Genes & Development
(http://www.genesdev.org).
"The objective of the study was to assign physiological functions to the small
family of PAR bZip transcription factors," explains Dr. Ueli Schibler,
principal investigator of the study and in whose lab the first PAR bZip
transcription factor was found nearly 15 years ago. The PAR bZip transcription
factor family is composed of three proteins (DBP, HLF and TEF), all of which
display distinct patterns of circadian accumulation: In tissues with high
amplitudes of circadian clock gene _expression (like the liver), PAR bZip
protein levels change up to 50-fold throughout the day. However, in the brain,
where clock gene _expression varies little, PAR bZip protein levels barely
change..
To explore the functional significance of the PAR bZip protein family, Dr.
Schibler and colleagues disrupted one, two, or all three of the PAR bZip genes
in mice. The single, double, and triple knock-out mice (as they are known)
appear normal, but it quickly became apparent that the triple knock-out mice
(i.e. those missing all three PAR bZip genes) have markedly short life spans:
50% died within two months, and less than 20% survived to one year. The cause
of early death, though, was not immediately apparent.
As Dr. Schibler recounts, "It was by serendipity that my two collaborators Fred
Gachon and Pascal Gos identified the cause of mortality. Both of them took very
meticulous notes, and in looking at their files noticed that more mice died on
Mondays and Thursdays, when the animal keepers clean the room hosting these
mice with the vacuum cleaner. Placing a cage with triple knockout mice and, as
a control, a cage with double knockout mice, close to a vacuum cleaner revealed
a tragedy when the vacuum cleaner was turned on: About half of the triple
knockout mice immediately started "wild-running" and then displayed terrible
spasms." Many of these animals died as a consequence of the sound-induced
epileptic attacks. In contrast, none of the DBP/HLF double knockout mice were
affected by the noisy vacuum cleaner.
The researchers monitored brain electrical activity in the mice to confirm
their observation that those mice lacking all three PAR bZip genes are prone to
epileptic seizures. The recording of electroencephalograms (EEGs) during
several days revealed that all of the triple knockout mice also suffered from
generalized spontaneous seizures (in addition to the sound-induced epilepsies).
Interestingly, though, DBP and HLF single knockout mice and DBP/HLF double
knockout mice are no more seizure-prone than wild-type (genetically normal)
mice. All examined mice lacking the TEF gene – even TEF single knockout
mice - show some abnormal EEG activities, but these only develop into
generalized (and frequently lethal) seizures when the other two PAR bZip
transcription factors are also lacking.
Further work by Dr. Schibler and colleagues revealed that the cause of these
epileptic attacks may lie in yet another gene, called Pdxk. The Pdxk gene
encodes an enzyme that converts vitamin B6 into its physiologically active
form, pyridoxal phosphate (PLP), and PLP is crucial for the metabolism of
several neurotransmitters. Dr. Schibler is quick to point out that "Although
vitamin B6 deficiency has been known to provoke epilepsies in humans and
laboratory rodents, PDXK misregulation has never been discovered thus far."
Indeed, the researchers found that Pdxk _expression is regulated by the PAR
bZip transcription factors in both the liver and the brain. Furthermore, Pdxk
_expression is abnormally low in the brains of PAR bZip triple knockout mice,
suggesting that the downregulation of Pdxk in these mice may be at least partly
responsible for their epilepsy.
The potential role for Pdxk misregulation in human epilepsy is even more
intriguing, given the close proximity of Pdxk to the CSTB gene, which is
thought to be responsible for the hereditary form of human epilepsy known as
"Unverricht-Lundborg Disease."
As Dr. Schibler explains, "It now becomes important to examine whether promoter
mutations in CSTB (expansion of a GC-rich dodecamer) can also influence the
_expression of the gene next door, namely PDXK. Clearly, with the limited
resolution obtained in human haplotype mapping, it cannot be excluded that
underexpression of PDXK contributes to the Unverricht-Lundborg disease."
While the scientific community considers this novel role for PAR bZip
transcription factors and Pdxk in epilepsy, Dr. Schibler's group is already at
work on the premature aging phenotype displayed by the triple knockout mice.
"We already have some ideas on what these circadian transcription factors do in
the liver, and we also have some clues (speculations) on why their elimination
might provoke premature aging. But we would like to finish our experiments
before spilling the beans."
###
Contact: Heather Cosel
coselpie@cshl.edu
Cold Spring Harbor Laboratory
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