Molecular basis of neurological disorders Flashcards
describe layout of a gene
5 prime untranslated region
transcribed into mrna but not translated
-start site for translation to occur
coding section of gene– exon, interrupted by introns (not in final message as removed by splicing)
stop codon followed by
3 prime untranslated region
what is a trinucleotide
and why do neurological diseases occur here
3 nucleotides repeated consecutively many times
repeated in any section of the gene
repetition in a number of sequences result in a disease
-eg. number of repeats increased
what is huntintons disease
symptoms
which part of brain affected
autosomal dominant
present midlife
involuntary
chorea
dystonia
behavioural changes
psych changes
gradual loss of cognition and death
striatum
atrophy of caudate nucleus and putamen
what is the genetic basis behind huntingtons
expansion of a trinucleotide repeat
CAG (which codes for GLUTAMINE)
–POLYGLUTAMINE in exon therefore protein is altered
why is extra glutamine harmful?
Huntingtin protein misfolds
aggregates
inclusion bodies
in protein:
beta pleated sheet with hydrogen bonds from one side of sheet to the other
R group lined up with R group on other strand of beta sheet
if both are glutamine- potential for additional hydrogen bonding– giving structure more stability which forms AGGREGATES
what is fragile x syndrome
symptoms
leading cause of inherited mental impairment
SINGLE GENE DISORDER on the X chromosome
affects men and women
-more severe for men as only one X chromosome
long face with prominent forehead and jaw
mitral valve prolapse
mental impairment
attention deficit
autistic like behaviour-tactile defensive, poor eye contact, HAND FLAPPING
What is the genetic basis behind fragile x syndrome
what is the role of the FMR1 PROTEIN
FRM1 gene (fragile x mental retardation)
trinucleotide CGG repeated in the 5’ untranslated region of gene
FMR1 protein is highly expressed in neurons
gene regulates BY REPRESSING mRNA translation so dont get xs protein
The FMR1 gene provides instructions for making a protein called FMRP. this protein regulates the production of other proteins by stopping the translation of other mRNA, by dampening down response to glutamate
in absence of FMRP (in fragile X) mRNA translation occurs in abundance, as xs glutamate signalling– get xs mRNA translation– lots of protein– FRAGILE X SYNDROME
The abnormally expanded CGG segment turns off (silences) the FMR1 gene, which prevents the gene from producing FMRP. Loss or a shortage (deficiency) of this protein disrupts nervous system functions and leads to the signs and symptoms of fragile X syndrome
What are some ways to potentially prevent loss of fragile x protein
block glutamate signalling
with GLUTAMTE ANTAGONIST
therefore block signalling
why are trinucleotides susceptible to expansion
unwound can form a HAIRPIN structure and form double helix on its own
what is genetic anticipation and give an example of a disease
signs and symptoms of a disease become more severe down generations, and appear at an earlier stage
myotonic dystrophy
-progressive muscle wasting and weakness
more expansion
why does genetic anticipation help clinically
Msh3 gene
dna mismatch repair gene
more copies=increase expansion
create an inhibitor to prevent expansion?
but it is important in other protection like colon cancer
What is an experimental treatment for huntingtin being done right now
antisense oligonucleotides
to block expression of protein that is causing problem
huntingtin gene and oligo causes hybridisation
this is then targeted for DEGRADATION and cant make protein if no mrna
reduced production of HTT
can use different antisense oligonucleotides for different diseases
what is interesting about early onset AD
early onset
inherited autosomally dominant
5% of all AD
also if have downs syndrome it is a high risk
gene present on chromosome 21? putting you at risk of AD
what protein is present on chromosome 21 (AD)
why is this an issue
AMYLOID PRECURSOR PROTEIN
more protein = more at risk of AD
protein concentrated in neurons regulating synapse formation
cleaved by different enzymes
normal:
cleaved by alpha secretase
sometimes:
also cleaved by beta and gamma secretase
forming amyloid beta peptide== aggregate outside the cell forming deposits
AD (familial):
in some families there are mutations in the APP to increase beta secretase cleavage
what gene mutations are associated with early onset familial AD
presenilin 1 (70%)
presenelin 2 (5%)
subunits of gamma secretase
APP (10-15%)
