Describe the two broad mechanisms by which neurodegenerative disorders develop?
Acquired (eg. cerebrovascular disease, alcholism)
Inherited: unstable repeat expansions
What are unstable repeat expansions?
Expansion of a segment of DNA within a specific gene, which consists of repeating units of three or more nucleotides in tandem
What is the difference between naturally occuring repeat regions and repeat expansions?
Repeat expansion occurs when the number of repeats increases beyond a certain threshold > associated with a condition
Why are unstable repeat expansions referred to as dynamic?
Size of expansion changes
Describe the phenomenon of anticipation?
Expansion size increases in following generations
Usually associated with ealrier onset and greater severity of symptoms
Describe the mechanism by which expansion of repeats occurs?
Which body system do unstable repeat expansions usually affect?
Describe the different ways in which unstable repeat expansions can affect a gene?
Non-coding repeats > loss of protein function > impaired transcription
Non-coding repeats that confer novel properties on RNA > toxic ganin of function
Repeats in codon > novel properties on protein > novel gain of function
Describe the general characteristics of neurodegenerative disorders caused by repeat expansions?
Loss of movement control
Describe the genetics of Huntington disease?
CAG repeat expansion in HTT gene of chrm 4
Repeat in exon 1 - CAG codes for glutamine
Describe the prevalence of HD?
1 in 10,000 to 20,000
Describe the onset of HD?
Describe the major features/symptoms of HD?
What is the normal role of the HTT gene?
Produces protein product - huntingtin
Seems to have roles in transcription
A lot we don't know about it
What is the expanded CAG huntingtin product referred to as?
Where does polyQ-huntingtin exert its toxic effects?
Medium spiny neurons in striatum of basal ganglia
Describe the appearance of a HD brain on imaging?
Initially starts in basal ganglia, but as disease progresses it spreads to whole brain
Describe the basic molecular pathology of HD?
PolyQ-huntingtin is cleaved by caspases > generates N-terminal fragments with altered conformation > TOXIC
Form aggregates and nuclear inclusions - may be protective?
Describe the genotype/phenotype corrleation in HD?
Normal: <26 repeats
Normal, mutable (paternal transmission): 27-35 repeats
Zone of reduced penetrance: 36-39 repeats
Affected: >39 repeats
Describe the effects of CCG interruptions in HD?
Don't code for glutamine > interrupt length of glutamine > can mitigate effects of CAG repeats and prevent onset of HD
How is HD clascially tested for?
PCR, gel electrophoresis and autoradiography
Describe the current method for HD testing?
PCR (fluorescent tagging), fragment analysis on capillary electrophoresis and fluoresence detection
Describe the major features and symptoms of spinal cerebellar ataxias?
Progressive degeneration of cerebellum, brain stem and spinocerebellar tracts
How are SCAs tested for?
Describe the genetics of Freidreich ataxia?
GAA repeat expansion in FXN gene on chrm 9
Repeat location within intron 1
Causes abnormal DNA secondary structure > reduced protein (frataxin) production
Describe the main features/symptoms of Friedreich ataxia?
Progressive limb and gait ataxia
What is the general age of onset for FA?
Describe the pathogenesis of FA?
Repeat expasnion causes decreased frataxin production
Causes mitochondrial iron accumulation > oxidative damage
Describe the FA genotype/phenotype correlation?
Normal: 5-33 repeats
34-65: premutation range
How is FA tested for?
Standard PCR - can be used because we are dealing with large numbers of repeats