Molecular Basis of Neurodegenerative Disorders Flashcards
Name examples of diseases that can arise from unstable trinucleotide repeat disorders
Fragile X syndrome, Huntington’s disease, spinobulbar muscular atrophy, spinocerebellar ataxia
Describe features of Huntington’s disease
Autosomal dominant condition that presents midlife with motor abnormalities (chorea and dystonia), behavioural and psychiatric changes, gradual loss of cognition and ultimately death. Areas of brain affected are; striatum (most seriously) with atrophy of the caudate nucleus and putamen
What is the trinucleotide repeat in Huntington’s Disease?
CAG repeats which causes a protein with extra glutamine present. (polyglutamine in coding region) This results in protein misfolding, formation of aggregates and inclusion bodies.
What occurs with complete lack of the Huntington protein?
It is also harmful for health it is thought the role of the huntington protein is to transport proteins along the cytoskeleton
What is Fragile X syndrome and its phenotype?
Leading cause of mental impairment. It is a single gene disorder on the X chromosome. It presents with long faces (prominent forehead and jaw), mitral valve prolapse, mental impairment (IQ of 20-60), attention deficit/hyperactivity disorder and autism like behaviours.
What is the molecular basis behind fragile X?
Trinucleotide repeat (CGG) in the 5 prime non-coding region which causes transcriptional silencing and a reduction in the Fragile X Mental Retardation gene 1 (FMR1)
What is the function of FMR1?
Highly expressed in neurons and it regulates mRNA translation in dendrites. Normally supresses translation of proteins however in Fragile X it doesn’t supress the translation and so it results in increased protein synthesis. Pathway is initiated by signalling from glutamate
Describe the expansion mechanisms
The triple repeats can develop hairpin conformations which is where there is base pairing between pairs on the same DNA strand.
What is genetic anticipation?
A phenomenon in which the signs and symptoms of a genetic condition tend to become more severe and/or present at an earlier age as the genetic condition is passed down generations
What is the molecular basis for Alzheimer’s disease?
- (FAMILIAL) APP mutations resulting in increased beta secretase cleavage and increased A beta peptides.
- (FAMILIAL) Mutations in Presenilin 1 and 2 is also associated with early onset AD as they affect the activity of gamma-secretase enzymes.
- In sporadic AD mutations in APOE, especially APOE4. Other genes involved are CLU, PICALM and CR1
What is the normal function of ApoE?
It is a cholesterol transport and clears Amyloid beta
What is the significance of TAU?
Tau stabilizes microtubules however in Alzheimer’s if becomes phosphorylated forming neurofibrillar tangles
What are Prion Diseases?
- Transmissible spongiform encephalopathy; eg Creutzfeld-Jacob disease, fatal familial insomnia and kuru.
- They are proteinaceous infectious diseases, an example of an infectious neuropathy
What is the molecular basis of prion diseases?
Conformational change of the bodys normal prion protein which will interact with the normal folded prion proteins and cause them to change conformation. There can then be neuron-to-neuron transmission of these mutated proteins.
What is the normal function of the prion protein?
Not sure but seen in synaptic membranes of neurons
