Genes and NeuronsNeurons and Gene Expression

RNA InterferenceGenes and Brain Functions

Genes in Schizophrenia

At least a third of our 20,000 genes that make the human genome are active(expressed) in the brain.

This is the highest proportion of genes expressed in any part of the body.

These genes influence the development and function of the brain, and ultimately control how we move, think, feel and behave.

Combined with the effects of our environment, changes in these genes can also determine whether we are at risk for a particular disease and if we are, the course it might follow.

The Genes in the Brain

Certain genes make proteins that in turn make neurotransmitters. Other proteins are important for establishing synapses or for disposing of

excess neurotransmitters (like the COMT gene).

Genes and Synapse Neurotransmission

DNA binding proteins (transcription factors, polymerase, nucleases)

Histone Proteins

Non-protein-coding RNA

Factors that Regulate Gene Expression in the Brain

Control(Regulatory) Genes in the brain

Some genes make proteins that act as housekeepers in the brain, keeping neurons and their networks in good working order.

-About 10% of the genes in the human genome encode DNA binding proteins.

-Some of these proteins recognize and attach to specific bits of DNA to activate gene expression (ex. transcription factors, polymerases, nucleases)

Histones are DNA binding proteins that act as a spools that keep the DNA in tight coils and thus suppress gene transcription and expression.

Methylation keeps the histones tight together. In this state the DNA cannot be transcribed/expressed. In order to be transcribed and expressed the histones must come apart (demethylation or acetilation).

Histone Proteins

Some genes encode small bits of RNA that are not used to make proteins, but are instead used to tell proteins what to do and where to go. These are called non-coding or RNA genes.

There are many more RNA genes than protein- coding genes

Non-coding RNA seems to be important inchronic neurologic and psychiatricconditions. Non-coding RNAs can be used (a techniquecalled RNA interference) in order to silencegenes that are associated with diseases.

Non-Protein Coding RNA (RNA Genes)

RNA interference is a gene silencing technique that takes advantage of the ability of small non-coding RNAs to modify gene expression.

RNA interference could be used therapeutically to power up a gene that has been abnormally silenced, or turn down one that has been overactive (such as neuregulin in schizophrenia or huntingtin in Huntington’s disease).

Future Applications of RNA Interference in Psychiatry?

RNA Interference:Purple-and-green non-coding RNA target cell surface receptors (purple) and deliver the RNA to the Dicer enzyme (orange) which cuts the RNA making it the right size to interfere with protein synthesis machinery of the cell, silencing or powering up a gene.

HAR1 is a gene active in the neurons during the development. Its mutations can lead to a condition similar to microcephaly in which the cerebral cortex fails to fold properly.

These genes are believed to have contributed to humans having significantly larger brains as compared to animals.

HAR 1 Gene Was Discovered in August 2006

Mutation of microcephalin or ASPM genes can lead to microcephaly.

For example, the ASPM gene makes a protein that is needed for producing new nerve cells in the developing brain. Alterations in this gene can cause microcephaly.

ASPM and Microcephalin Genes

Huntingtin GeneHuntingtin protein contributes to brain-derived neurotrophic factor (Bdnf) transcription in the cortical neurons that project to the striatum

Huntingtin might also facilitate vesicular BDNF transport from the cortex to the striatum. Mutations in this gene are responsible for Huntington’s Disease.

Superoxide Dismutase Gene(SODI)

SODI gene makes a protein that fights DNA damage in neurons.

Alterations in this gene are one of the causes of ALS.

The SODI gene is believed to hold important clues about why neurons die in ALS.

FOXP2 has been called the "language gene."

Several cases of developmental verbal dyspraxia in humans have been linked to mutations in the FOXP2 gene. In humans, mutations of FOXP2 cause a severe speech and language disorder.

fMRI analysis of these individuals shows underactivation of Broca's area and the putamen, brain centers thought to be involved in language.

Scientists have also looked for associations between FOXP2 and autism. 

FOXP2 Gene

Linkage studies show a number of places in the human genome where pieces of DNA are inherited along with the risk for schizophrenia.

Left are the chromosomes - red dots indicate regions with risk for schizophrenia in certain families and certain studies. Right are the identified genes in some of these regions.

Chromosomes and Genes Linked to Schizophrenia

The genes suspected of causing autism, schizophrenia and other mental illnesses are activated in the developing brain before birth, according to a major genetic analysis published Oct. 27, 2011 in the journal Nature.

For this study, researchers examined more than 1,300 tissue samples taken from 57 people at different stages of brain development, ranging from 40 days after conception to 82 years of age.

They discovered that a significant amount of the human brain is shaped before birth. For instance, the researchers found proof that genes linked to autism and schizophrenia are activated in “utero”.

 

Genes Involved In Autism and Some Mental Illnesses May Be Activated In Utero.

Velo-cardio-facial syndrom(VCFS) is characterized by increased frequency of schizophrenia and bipolar disorder.

VCFS is associated with deletions of area11 of chromosome 22.

The high prevalence of schizophrenia(30%) in this group suggests that the area11 of chromosome 22 might harbor genes relevant to the etiology of this condition.

Indeed, the COMT and proline dehydrogenase (PRODH) genes were discovered in this area. They are both associated with schizophrenia.

High Rates of Schizophrenia in Velo-Cardio-Facial Syndrome

Catecol-O-Methyl_Transferase(COMT) is an enzyme that metabolizes dopamine (just like MAO).

Its gene comes in two “flavors”(alleles) met and val. Individuals with Met/Met allele are more prone to cognitive

impairment and impulsivity than individuals with Val/Val alleles.

COMT Gene

Examination of the DNA from multiple family groups afflicted with schizophrenia has identified a link to the gene for neuregulin-1as being a key factor in schizophrenia.

The role of NRG 1 gene are summarized below along with observed phenotypes in schizophrenia.

Neuregulin 1 Gene(NRG 1)

Linked in the early 1990s to mental illnesses. Prevalent in a large Scottish family  in which over five generations many family

members had developed schizophrenia, bipolar disorder, and other mood disorders. Each family member diagnosed with mental illness also carried a mutated copy of DISC1 gene.

DISC 1 is important for the early development and growth of the infant brain. It participates in the regulation of cell proliferation, differentiation, migration, neuronal axon and dendrite outgrowth, mitochondrial transport, and cell-to-cell adhesion.

DISC 1 Gene

DAOA is a gene encoding a long non-coding RNA. It is one of the genes associated with schizophrenia.

It is also associated with bipolar disorder and other psychiatric phenotypes. 

DAOA Gene

A strong association was found between the expression of a particular dysbindin allele and schizophrenia.

However, the genetic link between dysbindin and schizophrenia has not been established in all the case control samples tested.

This implies that there are different genetic subtypes of schizophrenia with different disease allele frequencies in different populations.

Dysbindin Gene

The Reelin gene (RELN) is localized to chromosome 7 and is involved in the migration of new nerve cells during the fetal development of the neocortex.

Reelin controls the function of cadherins in cortical neurons. Cadherins act as a glue that allows cells to attach to each other as they move.

A radial glial cell (yellow)

sends out a process towards

a neuron (red) that contains

the extracellular protein reelin.

Reelin gene