1. Neurons and Gene Expression
RNA Interference
Genes and Brain Functions
Genes in Schizophrenia

2.  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.

3. 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).

4.  DNA binding proteins (transcription factors,
polymerase, nucleases)
 Histone Proteins
 Non-protein-coding RNA

5. 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)

6.  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).

7.  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 in
chronic neurologic and psychiatric
conditions.
Non-coding RNAs can be used (a technique
called RNA interference) in order to silence
genes that are associated with diseases.

8.  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).
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.

9.  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.

10. 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.

11. Huntingtin 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.

12. 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.

13.  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.

14.  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.

15. 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”.

16.  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.

17.  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.

18.  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.

19.  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.

20.  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.

21.  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.

22.  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.