Posts Tagged ‘White matter’

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from Ye et al., 2009:

HDAC1/2 genes encode proteins that modify the epigenome (make it less accessible for gene expression).

When HDAC1/2 functions around the HES5 and ID2/4 (repressors of white matter development) genes, the epigenetic changes (less acetylation of chromatin) helps to repress the repressors.

This type of epigenetic repression of gene expression (genes that repress white matter development) is essential for white matter development.

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An historic find has occurred in the quest (gold-rush, if you will) to link genome variation with brain structure-function variation.  This is the publication of the very first genome-wide (GWAS) analysis of individual voxels (voxels are akin to pixels in a photograph, but are rather 3D cubes of brain-image-space about 1mm on each side) of brain structure – Voxelwise genome-wide association study (vGWAS) [doi: 10.1016/j.neuroimage.2010.02.032] by Jason Stein and colleagues under the leadership of Paul M. Thompson, a  leader in the area of neuroimaging and genetics – well-known for his work on brain structure in twin and psychiatric patient populations.

In an effort to discover genes that contribute to individual differences in brain structure, the authors took on the task of statistically analyzing the some 31,622 voxels (per brain) obtained from high-resolution structural brain scans; with 448,293 Illumina SNP genotypes (per person) with minor allele frequencies greater than 0.1 (common variants); in 740 unrelated healthy caucasian adults.  When performed on a voxel-by-voxel basis, this amounts to some 14 billion statistical tests.

Yikes!  A statistical nightmare with plenty of room for false positive results, not to mention the recent disillusionment with the common-variant GWAS approach?  Certainly.  The authors describe these pitfalls and other scenarios wherein false data is likely to arise and most of the paper addresses the pros and cons of different statistical analysis strategies – some which are prohibitive in their computational demands.  Undaunted, the authors describe several approaches for establishing appropriate thresholds and then utilize a ‘winner take all’ analysis strategy wherein a single ‘most-associated winning snp’ is identified for each voxel, which when clustered together in hot spots (at P = 2 x 10e-10), can point to specific brain areas of interest.

Using this analytical approach, the authors report that 8,212 snps were identified as ‘winning, most-associated’ snps across the 31,622 voxels.  They note that there was not as much symmetry with respect to winning snps in the left hemispere and corresponding areas in the right hemisphere, as one might have expected.  The 2 most significant snps across the entire brain and genome were rs2132683 and rs713155 which were associated with white matter near the left posterior lateral ventricle.  Other notable findings were rs2429582 in the synaptic (and possible autism risk factor) CADPS2 gene which was associated with temporal lobe structure and rs9990343 which sits in an intergenic region but is associated with frontal lobe structure.  These and several other notable snps are reported and brain maps are provided that show where in the brain each snp is associated.

As in most genome-wide studies, one can imagine that the authors were initially bewildered by their unexpected findings.  None of the ‘usual suspects’ such as neurotransmitter receptors, transcription factors, etc. etc. that dominate the psychiatric genetics literature.  Bewildered, perhaps, but maybe thats part of the fun and excitement of discovery!  Very exciting stuff to come I’ll bet as this new era unfolds!

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The A-to-T SNP rs7794745 in the CNTNAP2 gene was found to be associated with increased risk of autism (see Arking et al., 2008).  Specifically, the TT genotype, found in about 15% of individuals, increases these folks’ risk by about 1.2-1.7-fold.  Sure enough, when I checked my 23andMe profile, I found that I’m one of these TT risk-bearing individuals.  Interesting, although not alarming since me and my kids are beyond the age where one typically worries about autism.  Still, one can wonder if such a risk factor might have exerted some influence on the development of my brain?

The recent paper by Tan et al., “Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2” [doi:10.1016/j.neuroimage.2010.02.018 ] suggests there may be subtle, but still profound influences of the TT genotype on brain development in healthy individuals.  According to the authors, “homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation.”

The FA (fractional anisotropy – a measurement of white-matter or myelination) results are consistent with a role of CNTNAP2 in the establishment of synaptic contacts and other cell-cell contacts especially at Nodes of Ranvier – which are critical for proper function of white-matter tracts that support rapid, long-range neural transmission.  Indeed, more severe mutations in CNTNAP2  have been associated with cortical dysplasia and focal epilepsy (Strauss et al., 2006).

Subtle changes perhaps influencing long-range information flow in my brain – wow!

More on CNTNAP2 … its evolutionary history and role in language development.

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arinlloydCelebrities and politicians are known for their love of the spotlight.  “Me, me, me!”  are the words to get ahead by in our modern media circus.   As well, it can even be – in the unglamorous world of science – where, in characteristically geeky form, the conventional wisdom is to shout, “my hypothesis, my hypothesis, my hypothesis!”.  Once, for example, I had a grad school professor say she was not allowed by her department to teach about glial cells in her brain development class.  Another distinguished professor once told me, “don’t even bother sending a grant in,  if it is focused on white matter“.   No sir, it appears that modern neuroscience shall only focus on one main hypothesis – the neuron doctrine and not on the lowly support cells (astrocytes, oligodendrocytes & microglia) that, actually, make up more than 90% of the human brain.  Hmmm, who would have thought to find such a cult of neuronal celebrity in the halls of academia?

With this in mind, I really enjoyed the recent paper “Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions” [doi:10.1523/jneurosci.0324-09.2009] by Maezawa and colleagues.  The authors point out several critical gaps in the literature – namely that the expression of MeCP2 (the gene that, when mutated, gives rise to Rett syndrome) in neurons does NOT account for all of the many facets of the syndrome.  For example, when MeCP2 is deleted only in neurons (in a mouse model), it results in a milder form of abnormal neural development than when deleted in all CNS cell types ( the full mouse syndrome: stereotypic forelimb motions, tremor, motor and social behavioral abnormalities, seizures, hypoactivity, anxiety-like behavior and learning/memory deficits).  Also, it is not possible to reverse or rescue these deficits when a functional version of MeCP2 is expressed under a neuron-specific promoter.  However, when re-expressed under its endogenous promoter – it is possible to rescue the syndrome (free access article).

The authors thus looked much more closely at the expression of MeCP2 and found that they could indeed visualize the expression of the MeCP2 protein in cultured ASTROCYTES – who are a very, very important type of support cell (just think of the personal secretary Lloyd to Ari Gold on the TV show “Entourage”).  The team then examined how astrocytes that lack 80% of the expression of MeCP2 might interact with neurons – the very cells they normally support with secretions of growth factors and cytokines.   It turns out that both normal and MeCP2-deficient neurons do not thrive when co-cultured with astrocytes that have weak MeCP2 expression.   The team reports that dendritic length is reduced after a day and also a fews days of co-culture,  suggesting that the MeCP2-deficient astrocytes are failing to provide the proper trophic support for their neuronal celebrity counterparts.  Short dendrites are generally considered a bad-thing since this would predict poorer connectivity, and poorer cognition across the brain.

Hence, it seems that the lowly astrocyte is far more important in understanding what goes wrong in Rett syndrome.  Ironically, in this case however, the celebrity status of the neuron remains untarnished as astrocytes can now be blamed for the consequences of MeCP2 mutations.  The authors suggest that treatment of Rett syndrome via astrocytes is a worthwhile avenue of investigation.  This new direction in the search for a cure will be an exciting story to follow!

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Within the genetic news flow, there is often, and rightly so, much celebration when a gene for a disease is identified.  This is indeed an important first step, but often, the slogging from that point to a treatment – and the many small breakthroughs along the way – can go unnoticed. One reason why these 2nd (3rd, 4th, 5th …) steps are so difficult, is that in some cases, folks who carry “the gene” variant for a particular disorder, do not, in fact, display symptoms of the disorder.

Huh? One can carry the risk variant – or many risk variants – and not show any signs of illness?  Yes, this is an example of what geneticists refer to as variable penetrance, or the notion of carrying a mutation, but not outwardly displaying the mutant phenotype.  This, is one of the main reasons why genes are not deterministic, but much more probablistic in their influence of human development.

Of course, in the brain, such complexities exist, perhaps even moreso.  For example, take the neurological condition known as dystonia, a movement disorder that, according to the Dystonia Medical Research Foundation, “causes the muscles to contract and spasm involuntarily. The neurological mechanism that makes muscles relax when they are not in use does not function properly. Opposing muscles often contract simultaneously as if they are “competing” for control of a body part. The involuntary muscle contractions force the body into repetitive and often twisting movements as well as awkward, irregular postures.”  Presently there are more than a dozen genes and/or chromosomal loci that are associated with dystonia – two of the major genes, DYT1 and DYT6 – having been identified as factors in early onset forms of dystonia.  Now as we enter the era of personal genomes, an individual can assess their (own, child’s, preimplantion embryo’s!) genetic risk for such rare genetic variants – whose effects may not be visible until age 12 or older.  In the case of DYT1, this rare mutation (a GAG deletion at position 946 which causes a loss of a glutamate residue in the torsin A protein) gives rise to dystonia in about 30-40% of carriers.  So, how might these genes work and why do some individuals develop dystonia and others do not?  Indeed, these are the complexities that await in the great expanse between gene identification and treatment.

An inspection of the molecular aspects of torsin A (DYT1) show that it is a member of the AAA family of adenosine triphosphatases and is related to the Clp protease/heat shock family of genes that help to properly fold poly-peptide chains as they are secreted from the endoplasmic reticulum of the cell – a sort-of handyman, general purpose gene (expressed in almost every tissue in the body) that sits on an assembly line and hammers away to help make sure that proteins have the right shape as they come off their assembly linesNot much of a clue for dystonia – hmm.  Similarly, the THAP domain containing, apoptosis associated protein 1 (THAP1) gene (a.k.a. DYT6) is also expressed widely in the body and seems to function as a DNA binding protein that regulates aspects of cell cycle progression and apoptosis.  Also not much an obvious clue to dystonia – hmm, hmm.  Perhaps you can now see why the identification of “the gene” – something worth celebrating – can just leave you aghast at how much more you don’t know.

That these genes influence an early developmental form of the disorder suggests a possible developmental role for these rather generic cogs in the cellular machinery.  But where? how? & why an effect in some folks and not others?  To these questions, comes an amazing analysis of DYT1 and DYT6 carriers in the article entitled, “Cerebellothalamocortical Connectivity Regulates Penetrance in Dystonia” by Argyelan and colleagues [doi: 10.1523/JNEUROSCI.2300-09.2009]. In this article, the research team uses a method called diffusion tensor imaging (sensitive to white matter density) to examine brain structure and function among individuals who carry the mutations but either DO or DO NOT manifest the symptoms. By looking at white matter tracts (super highways of neural traffic) throughout the brain the team was able to ask whether some tracts were different in the 2 groups (as well as a group of unaffectd, non-carriers).  In this way, the team can begin to better understand the causal pathway between these run-of-the-mill genes (torsin A and thap1) and the complex pattern of muscle spasms that arise from their mutations.

To get right to the findings, the team has discovered that in one particular tract, a superhighway known as “cerebellar outflow pathway in the white matter of lobule VI, adjacent to the dentate nucleus” (not as quaint as Route 66) that those participants that DO manifest dystonia had less tract integrity and connectivity there compared to those that DO NOT manifest and healthy controls (who have the most connectivity there).  Subsequent measures of resting-state blood flow confirmed that the disruptions in white matter tracts were correlated with cerebellar outflow to the thalamus and – more importantly – with activity in areas of the motor cortex.  The correlations were such that individuals who DO manifest dystonia had greater activity in the motor cortex (this is what dystonia really comes down to — too much activity in the motor cortex).

Thus the team were able to query gene carriers using their imaging methods and zero-in on “where in the brain” these generic proteins exert a detrimental effect.  This seems to me, to be a huge step forward in understanding how a run-of-the-mill gene can alter brain function in such a profound way.  Now that they’ve found the likely circuit (is it the white matter per se or the neurons?), more focus can be applied to how this circuit develops – and can be repaired.

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