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huntington's disease Flashcards

1
Q

what are they symptoms of huntingtons disease?

A
  • subtle changes in personality (irritible, disinhibition)
  • unreliability ar work, difficulty multitasking
  • increasing forgetfullness, restlessness, fidgeting
  • clumsiness/awkward movements
  • onset of chorea and motor incoordination
  • weight loss/muscle wasting
  • emotional/psyciatric problems
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2
Q

what is “chorea”?

A
  • hallmark symptom of huntingtons disease
  • characterized by jerky, involuntary movements
  • usually in the face, shoulders or hips
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3
Q

is HD an inherited or acquired disease?

A

inherited

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4
Q

what is the inheritance pattern of HD? what does this mean?

A
  • autosomal dominant

- means the child of an affected parent will have a 50% chance of inheriting the mutation that leads to this disease

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5
Q

what is the average clinical onset of HD?

A
  • 37 years

- can be anywhere from infancy to late 80s

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6
Q

what mental illness is typically seen with HD?

A
  • depression

- suicide rate is 5-10x general populations

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7
Q

what typically occurs 15-20 years after the clinical onset of HD?

A

severe mental and phsycial decline, resulting in death due to complications of falls/aspiration pneumonia

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8
Q

what is the prevalence of HD?

A
  • in western countries: 5-7/100,000

- appears to be less common in other populations

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9
Q

does HD affect males and females equally across all racial backgrounds?

A

yes

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10
Q

what is the de novo (not seen in parent) mutation rate for HD?

A

1-3% of cases arise from a newly acquired mutation

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11
Q

what is genetic anticipation?

A

a phenomenon where the clinical features of a hereditary disease develop at an earlier age and or with increased severity as it is transmitted from one generation to the next

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12
Q

what is juvenile onset huntington’s disease? is this a case of genetic anticipation?

A
  • HD before the age of 20
  • these patients typically see rigidity instead of chorea
  • this is an example of genetic anticipation
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13
Q

what were the major research findings concerning HD in 1983?

A
  • studies examining family pedigrees established that the HD gene is linked to a polymorphic DNA marker on human chromosome 4
  • gene was named the Huntington gene after Dr. George Huntington
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14
Q

what were the major research findings concerning HD in 1987?

A

-the huntington gene was localized to a small segement (exon 1) of chromosome 4, flanked by D4S10 and the telomere

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15
Q

what were the major research findings concerning HD in 1993?

A

found that the huntington gene contained a polymorphic trinucleotide CAG repeat that is expanded and unstable in HD chromosomes

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16
Q

with respect to genes, what is responsible for the formation of huntingtons disease?

A
  • the formation of trinucleotide CAG repeats

- these can be large and lead to the development of neurological diseases

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17
Q

how are trinucleotide repeat expansions formed?

A
  • during replication, the leading strand slips and stalls as it encounters highly repetitive DNA (trinucleotide repeat)
  • when it gets back to production it creates an extra looped portion (aka slipped strand structure)
  • thus the synthesized dna contains an expanded trinucleotide repeat region
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18
Q

are there different HD phenotypes?

A

yes

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19
Q

what do the different HD phenotypes depend on?

A

the amount of CAG repeats an individual has in the HTT gene

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20
Q

what phenotype is associated with 10-26 repeats?

A

none - this is the normal number of repeats in the HTT gene

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21
Q

what phenotype is associated with 27-35 repeats?

A

can be meiotically unstable in paternal transmission - so children of these men can inherit disease-associates repeats of 40+

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22
Q

what phenotype is associated with 36-39 repeats?

A
  • rare and associated with reduced penetrance

- some individuals develop HD and others dont

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23
Q

what phenotype is associated with 40+ repeats?

A

100% penetrance - will develop the disease if they live long enough

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24
Q

what phenotype is associated with 70+ repeats?

A

invariably cause juvenile onset HD

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25
Q

what is the biomarker used to test for HD? how is the test for this biomarker done?

A
  • biomarker = size of the CAG repeat region of Exon 1 of the HTT gene
  • PCR on a patients DNA sample, run result on electrophoresis gel and compare to healthy sample
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26
Q

there are many CAG repeat polyglutamine diseases (including HD) but all have different ______?

A

“normal” CAG repat numbers

-e.g. normal for HD = 10-35, while normal for SCA2 = >30

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27
Q

what is the difference btwn predictive and diagnostic testing for HD?

A
  • diagnostic testing occurs to make a diagnosis, typically when someone has unexplained symptoms of HD
  • predictive occurs to see if someone is at risk for developing the disease
  • e.g. if someone was diagnosed and their family members want to see if they are also at risk
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28
Q

what is the wild-type (unmutated) HTT gene involved in the normal biology of the cell? (4)

A

(1) transcriptional regulation
(2) vesicle trafficking (including axonal transport)
(3) downregulation of glutamate activity
(4) anti-apoptotic functions

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29
Q

how is wild-type HTT involved in transcriptional regulation?

A

influences transcriptional regulation through its interaction with an array of transcriptional factors
-e.g. regualtion of BDNF production

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30
Q

how is wild-type HTT involved in the downregulation of glutamate activity?

A
  • this includes NMDA receptors

- occurs through the interaction with postsynaptic density proteins

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31
Q

mutations in the huntingtin protein can result in what?

A

the loss of normal function and neurodegeneration

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32
Q

compare the clinical onset of individuals who inherit the HD mutation from both parents vs those who inherit the mutation from just one parent.
what do the results of this comaprison suggest?

A
  • both types of inheritance show similar age of onset for clinical symptoms and equivalent repeat expansions
  • suggests that both loss of normal function and gain of toxic function of the mutated hubtingtin contribute to pathogenesis of the disease
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33
Q

what are the 2 mechanisms involved in the pathogeneis of HD due to mutated huntingtin proteins?

A

(1) cleavage products: proteolytic cleavage of mutant HTT generates an N-term fragment containing the polyglutamine expansion
- disrupts cellular functions leading to pathogenesis
(2) aggregates: intra-cytoplasmic and intra-nuclear polyglutamate expansion undergoes a conformational transition to a beta-sheet dominant structure resulting in assembly into insoluble b-sheet-rich-amyloid like fibrils via oligomeric intermediates
- this causes cytotoxicity
- characterisitic featuer of HD

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34
Q

what are the toxic functions associated with HTT mutant proteins? (6)

A

(1) promoting mitochondrial dysfunction
(2) altered Ca influx/homeostasis
(3) protein accumulation
(4) transcriptional dysregulation
(5) altered RNA metabolism
(6) axonal transport defects

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35
Q

are trinucleotide repeats unique to HD?

A
  • no

- HD belongs to the subgroup (CAG)n polyQ of unstable trinucleotide repeat disorders

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36
Q

what composes the striatum?
where is it located?
what is its role?

A
  • putamen and caudate nucleus
  • located deep in the cerebral hemisphere
  • motor function, reward systems, etc.
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37
Q

what is the effect of HD on the striatum?

A

atrophy (shrinkage)

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38
Q

with HD, what neurons in the brain are selectively vulnerable to degradation? why?

A
  • medium spiny projection neurons

- bc these are located in the striatum

39
Q

describe spiny projection neurons

A
  • neurons from this class involved in the indirect pathway of movement degenerate early in the course of the disease
  • this sub-class contain enkephalin and GABA
40
Q

what is enkephalin? what are its effects?

A

naturalling occuring NT w potent pain-killing effects

41
Q

what is the indirect pathway of movement?

A

neuronal circut through the basal ganglia and associated nuclei within the CNS that helps prevent unwanted muscle contractions from competing with voluntary movements

42
Q

are medium spiny protejction neurons the only type of neurons effected by HD?

A
  • no

- also large cortical neurons (cerebral cortex)

43
Q

what is the relationship btwn 60 or more CAG repeats and age of onset?

A

clear relationship - typically see onset before the age of 20 (juvenile HD)

44
Q

what is the relationship btwn 55 or less CAG repeats and age of onset?

A
  • realtionship is weaker - repeat size not always predicitve of age of onset
  • in general, the less repeats, the lower the age of onset
45
Q

size of the CAG expansion in the HTT gene is influenced by what?

A

whether the repeat is transmitted by the mother or the father

46
Q

what repeat size is seen with maternal transmission?

A

nearly equal numbers

47
Q

what repeat size is seen with paternal transmission?

A
  • meiotic repeat instability has the tendency towards larger expansion
  • why some kids get it when dad didn’t appear to have it
48
Q

what are ethical issues of a child being tested for HD when their parent has it?

A
  • may not get it
  • insurance concerns
  • lack of treatment
49
Q

is there a cure for HD?

A

nope

50
Q

modern treatment for HD can be categorized into 3 groups, what are they?

A

(1) symptom management
(2) functional targeting
(3) aggregate dysruption/prevention

51
Q

describe generally symptom management

A
  • predominant method
  • common target = chorea
  • usually treated via dopamine depletion
52
Q

describe generally functional targeting

A

aims to reverse functional changes that are resulting from mutant protein aggregates

53
Q

describe generally aggregate disruption / prevention

A

aim to target the underlying problem by directly disrupting the amount of aggregate protein or preventing the mutant protein from forming

54
Q

what is tetrabenazine

A

depletes dopamine levels in the brain

55
Q

what is the primary drug used to treat chorea

A
  • tetrabenazine

- decreased symptoms by 23.5%

56
Q

what are the 2 mechanisms employed by tetrabenazine to treat HD?

A

(1) vmat binding: normally vmat proteins package dopamine into vesicles
- tetrabenazine binds vmats, preventing dopamine packaging, preventing the transport of dopamine to cell surfaces
(2) receptor binding: normally D binds receptors trigerring downstream signalling in the receiving nerve cell
- tetrabenazine competes w D by binding the receptors on the nerve cell
- this blocks D from binding and passing on electrical signals

57
Q

what are the adverse effects of tetrabenazine?

A

depression/sedation

58
Q

describe surgical intervention as a functional approach to treat HD

A
  • deep brain stimulation = where thin electrodes are placed through the skull into the brain
  • pulse generators places beneath the skin supply electrical impulses to the brain, acting as a pacemaker to reset the firing of neurons
59
Q

what are the disadvantages to deep brain stimulation?

A

exceedingly invasive intervention for minimal gain

60
Q

describe fetal cell transplantation as a functional approach to treat HD

A

involves replacing dead neurons with sterotaxic injections of fetal neuroblasts (typically from pig fetuses) into the striatum

61
Q

what are the disadvantages to fetal cell transplantation?

A

also massively invasive and there is a need for multiple administrations

62
Q

describe aggregate disruption and prevention treatment at the DNA level

provide an example

A
  • requires the use of specific dna recognition elements to bind a sequence of interest, coupled with nuclease activity to disrupt aggregate transcription
  • e.g. CRISPR-Cas9 approach to fix the mutation at the gene level
63
Q

what are disadvantages to dna level treatment?

A

off-target effects

64
Q

describe aggregate disruption and prevention treatment at the RNA level

provide examples

A

e.g. siRNA (rna interference)
or antisense oligonucleotide (ASO) approaches
-both approaches block the production of the mutant protein through cleaving or degrading mRNA or through supression of translation

65
Q

what are disadvantages to rna level treatment? (3)

A
  • off-target effects
  • overloading og endogenous RNAi pathways
  • autoimmune complications
66
Q

describe aggregate disruption and prevention treatment at the protein level

A
  • orally bioavailable and small molecules that can interfere with transcription/translation of HTT are currently an active area of research
  • still in preclinical phase - need to cross blood-brain barrier and are invasive
67
Q

what are zinc finger proteins?

A

small proteins with a variety of domains which allow their involvement in many cellular processes

68
Q

what are zinc finger proteins used for?

A
  • the treatment of aggregate formation

- specific to HD - reduce the amount of mutated HTT produced

69
Q

how do zinc finger proteins work in the treatment of HD?

what type of treatment is this?

A
  • dna approach
  • these proteins can be designed to selectively bind CAG repeats above a certain number
  • this prevents expression mutated HTT and reduce its production, while preserving normal versions of HTT
70
Q

what is an advantage of zinc finger proteins as treatment for HD?

A

wouldn’t have to design for each patient - it would work for any patient above a specific number

71
Q

how does CRISPR-Cas9 gene editing work as treatment for HD?

what is necessary for this treatment?

can everyone be treated this way?

A
  • make guide RNA to match target, add it and cas9 to target protein, cas9 snips target rna and the space is relaced with good rna
  • can selectively target nucleotide polymorphisms found within the HTT gene of an individual with a disease
  • requires you to know the sequence of both copies of the HTT gene for each individual needing treatment
  • only people with polymorphisms that can differentiate the two alleles can be treated this way
72
Q

what is the advantage of CRISPR-Cas9 treatment for HD?

A

permanent removal of the genetic lesion

73
Q

what are the disadvantages of CRISPR-Cas9 as treatment for HD? (3)

A
  • highly personalized therapy - needs to be designed for each patient
  • off-target effects
  • can’t stop the enzyme cutting properties after alterations are complete
74
Q

what are the general benefits of dna therapy? (4)

A
  • single adminsitration for long-term treatment
  • single drug for all mutation carriers
  • has potential to block all pathogenesis if treated early
  • possibility of germline fix
75
Q

what are the general limitations of dna therapy? (6)

A
  • invasive
  • irreversible
  • off-target effects
  • long-term inflammatory/immune response risk
  • prolonged nuclease activity
  • expensive to tailor for each patient (CRISPR-Cas9)
76
Q

how does ASO work as treatment for HD?

A
  • use allele specific oligonucleotides (ASO) which leads to ds rna formation
  • ds rna is cleaved by RNAse H1, preventing formation of the HTT protein, slowing disease progression
  • can use ASOs at the allele of interest, at the transcription start site, or to interfere with splicing
77
Q

how does siRNA work to treat HD?

A

directly cleave rna to prevent the formation of HTT proteins

78
Q

what are the general benefits of rna approaches to treatment of HD? (2)

A
  • single drug for all mutation carriers

- selective silencing of mutant allele

79
Q

what are the general limitations of rna approaches to the treatement of HD? (5)

A
  • invasive
  • off-target effects
  • immune response to ds rna
  • overload of endogenous RNAi pathway elements
  • requires repeat administration (ASO)
80
Q

describe the “intrabody generation” direct protein approach to HD treatment

A

intrabodies can be created against the mutant version of the HTT protein and repeatedly injected into the striatum

81
Q

describe the “PROTACs” direct protein approach to HD treatment

A

proteolysis targeting chimera proteins (PROTACs) can bind proteins and induce selective intracellular proteolysis

82
Q

describe the “ubiquitin ligases” direct protein approach to HD treatment

A

by linking chimeras of protein-specific targeting elements with ligases, proteins can be selectively targeted for degradation

83
Q

what is autophagy?

A

the natural, regulated mechanism of a cell that degrades unnecessary or dysfunctional cellular components

84
Q

describe the indirect protein approach of “inducing autophagy” for HD treatment

A
  • idea is the removal of the HTT protein through stimulation of the autophagy system
  • initiation of the autophagy system triggers the formation of phagophoes, which engulf mutant aggregate prone proteins
  • these then fuse with lysosomes where the contents are degraded bu acidic lysosomal hydrolases
85
Q

what process in mice demonstrated stimulation of the autophagy system

A

fasting - not tested in humans yet

86
Q

what are the general advantages to protein approaches for HD treatment? (2)

A
  • selecitve targeting of proteins for degradation

- potential for diet-based decreases in mutant HTT aggregates

87
Q

what are the general disadvantages to protein approaches for HD treatment? (2)

A
  • invasive

- still in preclinical phases

88
Q

what are the treatments that affect dna –> rna

A

CRISPR-Cas9

zinc finger proteins

89
Q

what are the treatments that act directly on rna

A

ASO

siRNA

90
Q

what are the treatments that affect protein –> aggregated protein

A

ubiquitin ligases
intrabody generation
PROTACs

91
Q

what are the treatments that directly affect disease proteins

A

autophagy

92
Q

protein deposition is a common feature of AD, HD and prion diseases, however, each disease is assoicated with a specific protein and region of the brain.
what are they?

A 
AD: occipital/temporal
-amyloid-beta, tau proteins
HD: temporal
-HTT protein
prions: parietal/frontal 
-PrP (prion protein)
93
Q

what are the 5 stages of HD?

A 
stage 1: preclinical 
stage 2: early
stage 3: middle 
stage 4: late
stage 5: end-of-life

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