Rett Syndrome

[Guest guest]

> >> Study Offers New Insight Into Rett Syndrome

>> Rett Syndrome Research Foundation funded study leads to breakthrough for

>> Rett syndrome research

>> http://www.eurekalert.org/pub_releases/2003-10/wifb-son102703.php

>>

>> Rett Syndrome is a major cause of mental retardation in girls.

>> Although researchers have identified the protein involved in the disease,

>> its exact role remains a mystery. Now, a group of researchers from

>> Children's Hospital Boston and Whitehead Institute of Biomedical Research

>> have identified the protein's function, a discovery the scientists say

>> could

>> be the first significant advance in Rett Syndrome research in years.

>> The study, reported in this week's issue of the journal Science,

>> describes how the protein in question controls gene expression in normal

>> central nervous system cells. Researchers suspect that mutations in the

>> protein impair its ability to regulate genes during a critical stage of

>> brain development.

>> “We think that this deregulation may be responsible for some of the

>> defects that we see in Rett patients,†says Greenberg, director of

>> the Children's Hospital group and a lead author of the study.

>> A neurological disorder causing mental retardation as well as

>> cerebral-palsy and autism-like symptoms, Rett Syndrome affects one out of

>> approximately 15,000 female babies worldwide. Current therapies, including

>> medications that help prevent seizures, treat some of the symptoms but not

>> the disease.

>> Researchers have long known that mutations in a protein called MeCP2

>> somehow cause the disease, but until recently, little was known about how

>> the protein worked. Previous lab experiments demonstrated that MeCP2 binds

>> to genes that have undergone methylation (a fundamental biological process

>> in which the cell disables genes it doesn't use by modifying them with

>> methyl). Like a biological deadbolt, MeCP2 adheres to these methylated

>> genes, further preventing them from ever activating. As a result,

>> scientists

>> theorized that MeCP2 was what they call a “long-range gene repressor.â€

>> Rudolf Jaenisch's Whitehead lab has studied this protein for years,

>> demonstrating that when MeCP2 is disabled in mice, the animals manifest

>> Rett-like symptoms. But they couldn't figure out why this happens, and they

>> couldn't find the exact genes that MeCP2 targets.

>> At the same time, Greenberg, who also is a professor of neurobiology

>> at Harvard Medical School, was studying a central nervous system gene that

>> is highly active in infants age 6 to 18 months -- the same age that Rett

>> symptoms first appear. Greenberg noted that this gene, called BDNF,

>> constantly flips back and forth between an “on†state, where it rapidly

>> produces protein, and an “off†state, during which it's silent.

>> “We knew a lot about how it was turned on,†says Greenberg, “but we

>> wanted to know what kept it off.â€

>> + Article continues:

>> http://www.eurekalert.org/pub_releases/2003-10/wifb-son102703.php

>> * * *

>>

>>

>

[Guest guest]

Getting a Read on Rett Syndrome

Greg

Scientists are beginning to find clues to how a mutated gene may cause

cognitive and movement problems to appear in seemingly healthy young girls

A child's first birthday party is supposed to be a happy occasion. But

that's when many parents of girls with Rett syndrome begin to notice

that something is wrong with their daughters, says Carolyn Schanen, a

medical geneticist at Nemours Biomedical Research in Wilmington,

Delaware. In a gaggle of excited toddlers, a girl with Rett can " just

seem a little flat, " Schanen says. " They're not as animated; they're not

as interactive.

" And things quickly go downhill from there.

Rett syndrome is a genetic disorder that strikes roughly one in 10,000

girls just as they are beginning to walk and talk. After developing

normally for about a year, girls with the syndrome regress, losing any

words they've learned as well as the ability to make purposeful

movements. They end up with severe mental and physical disabilities and

require full-time care.

In 1999, researchers led by Huda Zoghbi at Baylor College of Medicine in

Houston, Texas, linked the devastating disorder to mutations in a gene

called MECP2 on the X chromosome. Rett syndrome is not inherited; the

mutations arise unpredictably. Boys with a disabling mutation in their

single MECP2 gene often die within a year or two from respiratory

failure, but girls, protected somewhat by having a good copy of the

MECP2 gene on their second X chromosome, can live into their 60s and

even 70s, Zoghbi says.

In recent years, researchers have begun to understand how mutations in

this single gene can cause the syndrome's variety of neurological

impairments. One tantalizing lead suggests that mutations in MECP2

derail brain development by interfering with a growth factor needed to

fine-tune synaptic connections. Yet even as they grapple with the

complex molecular biology behind Rett syndrome, scientists are exploring

hints that the disorder, or at least some of its symptoms, may one day

be treatable.

Several research teams have also recently found MECP2 abnormalities in

people with autism and related disorders, suggesting that the insights

gained from studying this gene are not limited to Rett syndrome. The

protein encoded by MECP2, called MeCP2, is normally incredibly abundant

in neurons, says Bird, a molecular biologist at the University of

Edinburgh, U.K., whose group discovered MeCP2 in the early 1990s. " I

think we have a lot to learn biologically about what it does, and I

think it's going to tell us quite a lot about the brain, " he says.

Stereotypical. Girls with Rett syndrome often exhibit repetitive

handwringing.

CREDIT: ALAN PERCY/UNIVERSITY OF ALABAMA, BIRMINGHAM

Sliding backward

Rett syndrome is especially traumatic for parents because a girl who

develops it initially seems healthy, Schanen says. Most hit early

developmental landmarks such as grasping objects, uttering words of the

" mama " and " dada " variety, and trying to walk. But sometime between 6

and 18 months, they enter a regression phase that can last a year or

more. Girls who once loved to turn the pages of a book as a parent read

to them can make only stereotyped wringing movements with their hands,

Schanen says. During their regression, girls often become withdrawn,

anxious, and irritable. They frequently become more social later in

life, but other problems persist, including profound cognitive and

movement deficits and breathing abnormalities.

Hundreds of MECP2 mutations have been associated with Rett syndrome.

Some render the gene unreadable, leaving cells unable to manufacture its

protein. But others cause cells to make abnormal forms of MeCP2, and

still others cause cells to make too much of the protein. Remarkably,

all three types of mutations cause similar symptoms. Moreover, a few

published studies have linked abnormalities in the gene to other forms

of mental retardation, juvenile-onset schizophrenia, and seizure

disorders. At the October meeting of the American Society of Human

Genetics, a team from Baylor (not including Zoghbi) reported finding

MECP2 abnormalities in 1% of a sample of autistic children. The bottom

line, says Zoghbi: " This is a protein you just don't want to mess with. "

How could defects in this protein or a lack of it lead to the diverse

symptoms of Rett syndrome, let alone other disorders? MeCP2 is one of

several so-called methyl-CpG-binding proteins, which are best known as

gene silencers: They turn off genes by binding to nearby regulatory

regions of DNA. Thus, one approach to unraveling Rett syndrome has

focused on identifying the specific genes that would normally be turned

off by MeCP2.

Several such targets have been found, but the one that has attracted the

most attention so far is the gene for brain-derived neurotrophic factor

(BDNF). This growth factor promotes the survival of neurons and has

important roles in brain development and in synaptic changes that

underlie learning and memory. " BDNF is the sexy brain gene, " says Bird.

" It has all the right credentials " to cause many of the problems seen in

Rett syndrome. In 2003, two research teams reported in Science that

MeCP2 normally suppresses BDNF expression in cultured mouse neurons (31

October 2003, pp. 885 and 890). That fit with MeCP2's proposed role as a

gene silencer and suggested that mutations in its gene cause

neurological problems by allowing too much BDNF to build up in the brain.

Complicating the picture, however, in the 2 February 2006 issue of

Neuron, researchers led by Qiang Chang and Rudolf Jaenisch of the

Whitehead Institute for Biomedical Research in Cambridge,

Massachusetts--authors of one of the 2003 Science papers--reported

abnormally low levels of BDNF in a strain of mice missing the mouse

version of MECP2, called Mecp2. These mice exhibit several features of

Rett syndrome, including reduced brain weight and hind-limb clasping, a

behavior reminiscent of the repetitive handwringing in Rett girls. The

same symptoms appeared when Jaenisch's team selectively disabled the

BDNF gene in the forebrains of mice. However, boosting BDNF production

in mice missing Mecp2 restored mobility and extended their life spans.

More evidence of interplay between MeCP2 and BDNF comes from a study in

the 19 October 2006 issue of Neuron by Zhaolan Zhou and

Greenberg at Children's Hospital Boston and colleagues. They report that

neural activity triggers a chemical modification, phosphorylation, of

MeCP2 that detaches it from BDNF's regulatory region, thereby turning on

production of the growth factor. Preventing MeCP2 phosphorylation

interfered with the protein's ability to regulate the growth of

dendrites, the branches on neurons that receive synaptic connections

from other neurons, the researchers also found. The findings suggest

that MeCP2 is a key player in regulating gene expression in response to

neural activity, Greenberg says.

Go time. Neural activity causes MeCP2 phosphorylation (bottom), allowing

gene transcription to proceed.

CREDIT: P. HUEY/SCIENCE

In his view, the emerging picture of Rett syndrome suggests a breakdown

of what neuroscientists call experience-dependent plasticity. The

earliest stages of brain development, in which neurons form their

initial connections, proceed largely according to genetic plans. In

later stages, neural activity triggered by an animal's interactions with

its environment fine-tunes neural connections, strengthening effective

synapses and weeding out ineffective ones. Early life experience

literally alters the brain's wiring, and Greenberg suspects that MeCP2

plays a key role in this process by regulating genes such as BDNF. In

Rett syndrome, however, MeCP2 protein is absent or nonfunctional, and

genes lose their oversight. " If you have BDNF and these other genes

coming on at the wrong time, you're going to get miswiring of the

nervous system, " Greenberg says. It's no coincidence, he says, that the

onset of Rett syndrome happens at about 1 year of age, a time when

experience-dependent plasticity is in full swing in the human brain.

Beyond BDNF

Still, many researchers, including Greenberg, feel certain that Rett

syndrome is not caused by BDNF abnormalities alone. Disruptions of BDNF

and experience-dependent plasticity could conceivably account for

several core features of Rett syndrome, including smaller brain size and

movement difficulties, says Altschuler, a neuroscientist at the

University of Michigan, Ann Arbor, and research director for the

International Rett Syndrome Association. " But then there are lots of

other things that for parents are very much a part of Rett syndrome, "

including severe constipation, breathing abnormalities, and anxiety,

says Altschuler, who has a daughter with the disorder.

A clue about what else goes awry in Rett syndrome appears in the 18

October Journal of Neuroscience. Katz of Case Western Reserve

University in Cleveland, Ohio, and colleagues report abnormal secretion

of several cell-signaling molecules in mice missing the Mecp2 gene.

Katz's team first examined BDNF secretion in neurons isolated from a

part of the vagus nerve involved in controlling respiration. Although

these neurons have reduced stores of BDNF in 35-day-old mice missing

Mecp2, the cells release a greater proportion of what they have.

The neurons may be trying to compensate for their low levels of BDNF,

Katz says, but he suspects there's something else going on. His team

also found excessive secretion in chromaffin cells in the adrenal gland.

These cells release adrenaline and other compounds that mediate the

body's stress response. The findings suggest that Rett symptoms such as

abnormal breathing and anxiety have more to do with cells' ability to

secrete signaling molecules, including BDNF, than with their ability to

make them in the first place, Katz says.

Stunted branches. Mouse hippocampal neurons (green) grow dendrites with

fewer branches when MeCP2 is blocked (right) compared to when the

protein is active (left).

CREDIT: Z. ZHOU ET AL., NEURON 52, 255 (2006)

A new study by Zoghbi's team provides additional clues about Rett

syndrome's anxiety symptoms. Her lab had noticed that mice with a

truncated Mecp2 gene, resulting in a malfunctioning protein, were

unusually averse to handling. Zoghbi's graduate student McGill

then found that the mutant mice have elevated levels of corticosterone,

a stress hormone. Additional experiments revealed that MeCP2 normally

suppresses the gene for corticotropin-releasing hormone (CRH), which

stimulates the adrenal glands to release corticosterone and other stress

hormones. In the Mecp2-mutant mice, the CRH gene is overactive, the

researchers reported online 15 November in the Proceedings of the

National Academy of Sciences.

Other researchers have recently reported high stress-hormone levels in

the urine of girls with Rett syndrome. And given that chronic stress is

bad for the brain, it's possible that correcting the overactive stress

response could alleviate other cognitive symptoms of Rett syndrome,

Zoghbi says. Her lab is now testing drugs that block stress hormones in

Mecp2-mutant mice.

Bird is also investigating whether Rettlike symptoms can be reversed. He

and colleagues have created a strain of mice in which the Mecp2 gene is

reversibly inactivated and can be turned back on after symptoms have

developed. But even if the symptoms disappear when the gene is restored,

the work won't yield a therapy for people with Rett syndrome anytime

soon--the sophisticated genetic tricks used in the mice aren't available

yet in humans.

Even so, many researchers express optimism that girls with Rett syndrome

have substantial numbers of healthy neurons that can form working

circuits if coaxed in the right way. Based on her clinical experience,

Schanen says it's something she has long suspected. " My interest in Rett

syndrome started because when I looked at these little girls, it wasn't

like the lights are on and nobody is home; it's like the lights are on,

there's somebody in there, and I just can't get them to come to the door. "