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PMCOL 412 > HD I > Flashcards

HD I Flashcards

1
Q

HD is a genetic neurodegenerative disorder characterized by:

A
  • motor symptoms
  • behavioral and psychiatric disturbances
  • cognitive dysfunction
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2
Q

Prevalence of ______ in Caucasian populations

A

1 in 10000

rare but most common genetic neurodegenerative disease

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3
Q

2 types based on age of onset

A

Age of symptoms onset:

  • Adult form: 35-45 years
  • Juvenile form: <20 years (~10% of HD cases)
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4
Q

Average age of onset for adult HD

A

35-45 years

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5
Q

Age of onset for junvenile form

A

<20 years

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6
Q

Time from onset to death

A

Inexorably progressive: death 15-20 years after onset

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7
Q

Hallmarks of HD

A

progressive motor symptomatology

different b/t adult and juvenile HD

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8
Q

Motor Symptomology seen in adult onset HD

A

involuntary choreic movements, impaired co-ordination

of voluntary movements affecting gait, speech and swallowing.

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9
Q

Motor Symptomology seen in juvenile HD

A

bradykinesia, rigidity, dystonia, epileptic seizures

chorea is often ABSENT

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10
Q

Non-motor features of HD

A
  • Cognitive dysfunction: learning impairment, reduced ability to plan and organize, difficulty concentrating on tasks
  • Behavioural and psychiatric disturbances: change in personality, depression, increased tendency to commit suicide, psychoses and schizophrenia in 10% of patients
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11
Q

Cognitive dysfunction (meaning)

A

learning impairment, reduced ability to plan and organize, difficulty concentrating on tasks

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12
Q

Behavioural and psychiatric disturbances (meaning)

A

change in personality, depression, increased tendency to commit suicide, psychoses and schizophrenia in 10% of patients

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13
Q

Clinical features of HD

A
  • Motor symptoms (differ b/t adult and juvenile HD)
  • Cognitive dysfunction
  • Behavioural and psychiatric disturbances
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14
Q

T/F: All symptoms progress at the same rate

A

FALSE

progression if different symptoms over the disease course

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15
Q

Chorea

A

‘dance’ in ancient greek

movement resembles a dance

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16
Q

HD neuropathology–areas affected

A

Most affected: the striatum, with gross atrophy of the caudate nucleus and the putamen.
Other affected areas: cortex,
Areas affected w/ disease progression: the lateral globus pallidus and the Purkinje cells in the cerebellum

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17
Q

Atrophy of ____ starts early on in prodromal HD patients

A

White matter

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18
Q

HD brain would show atropy of….

A

white, grey matter and striatum

further areas: cortex, cerebellar Purkinje cells, globus pallidus

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19
Q

In HD, the selective dysfunction of ____ neurons progresses to the degeneration of these neurons

A

striatal

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20
Q

In adult onset HD, loss of _______ ) in the striatum determine disruption of the _____, ____ firing of thalamo-cortical neurons and overall _____ movement

A

Enk+ GABAergic neurons (D2R-expressing); indirect pathway; increasing; increased

In adult onset HD, loss of Enk+ GABAergic neurons (D2R-expressing) in the striatum determine disruption of the indirect pathway, increased firing of thalamo-cortical neurons and overall increased movement (and chorea)

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21
Q

With progression of the adult form, both ___ and____ neurons die off, disrupting both the indirect
and direct pathways and producing an overall _____ in movement and the characteristic ____ in later disease stages

A

Enk+ (D2R-expressing) and SP+ neurons (D1R-expressing); decrease; rigidity

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22
Q

Why is chorea not present in juvenile HD

A

In juvenile HD, both kinds of striatal neurons degenerate
from the start, which is why chorea is usually not associated with juvenile HD.
go straight to bradykinesia and rigidity

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23
Q

Early adult HD

A

chorea and dyskinesia

D2R-expressing neurons lost

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24
Q

Late Adult HD

A

Bradykinesia and rigity

Both D1R and D2R-expressing neurons lost

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25
Q

HD is due to an _______ mutation in the___ gene,

which codes for a protein named _____

A

autosomal dominant; HD; huntingtin (HTT)

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26
Q

Normal HD gene has ___ ____ repeats

A

<36 CAG repeats

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27
Q

Adult-onset HD gene has ___ ___ repeats

A

36-55 CAG repeats

28
Q

Junvenilt HD gene has ___ ___ repeats

A

56-120 CAG repeats

29
Q

CAG protein repeats determine the length of ____ and proteins containing extended ___ are ___ to neurons and associated with ____

A

PolyQ; PolyQ; toxic; neurodegeneration

30
Q

Why are more CAG repeats bad

A

Because more CAG = longer PolyQ and polyQ containing proteins are toxic to neurons and cause neurodegeneration

31
Q

of polyQ in different Disease states (non-HD, adult-onset and juvenile)

A

Non-HD: <36 Q
Incomplete penetrance: 36-39 Q
Adult-onset: 36-55 Q
Juvenile: 56-120 Q

32
Q

T/F: A predictive genetic test can establish the number of CAG repeats inherited

A

True

33
Q

In normal HD # of Qs

A

normally 36 CAG repeats in the coding region (1st exon)

Translated into polyglutamine (polyQ) in huntingtin protein

34
Q

Relationship between # of CAG repeats and HD onset

A

more CAG repeats (and therefore longer PolyQ) = earlier onset

35
Q

T/F: all cases of HD are genetic

A

TRUE

36
Q

What is Huntingtin (HTT)

A
  • a 348 kDa (big) cytosolic protein, however it may associate with endocytic membranes and vesicles and with the plasma membrane (can also be shuttled in and out of the nucleus)
  • expressed in majority of tissues, in neural and non-neural cells
37
Q

What factors can influence HTT movement into the nucleus

A

stress–incl. heat, lack of neurotrophic factors

38
Q

HTT is a ___ protein involved in…

A 
Scaffold protein involved in:
• Vesicle trafficking
• Axonal transport
• Transcriptional regulation
• Stress responses
• Autophagy
• Regulation of apoptosis (anti-apoptotic)
• DNA damage responses
39
Q

T/F: HD is caused by both the loss of normal
huntingtin functions and the newly acquired
toxicity of mutant huntingtin (gain-of-function)

A

TRUE

40
Q

Normal functions that are lost

A
  • Axonal Transport regulation
  • Transcriptional regulation of neural genes and BDNF
  • Anti-apoptotic functions
41
Q

How are normal functions affected

A

Loss normal function of HTT due to aberrant conformation/interactions

42
Q

How are toxic functions gained

A

They result from the expanded polyQ region

43
Q

Gained TOXIC functions include:

A

Formation of protein aggregates

  • Impaired Mitochondrial metabolism
  • Exitotoxicity
  • Trascriptional dysregulation
  • Aberrant cell signaling
  • Impaired synthesis of gangliosides
44
Q

How does increased PolyQ change the conformation of HTT

A

Expanded polyQ stretches tend to misfold and to undergo a process of fibrillation and aggregation

45
Q

T/F: aggregates of mutant HTT can have a beneficial role

A

TRUE
Aggregates may have a beneficial role, acting as a
“sink” for more toxic soluble forms of huntingtin
(monomeric form or oligomers of the mutant protein)
Aggregates may be protective to scavenge the more toxic forms

46
Q

Most toxic forms of Mutant HTT

A

monomeric form or oligomers of the mutant protein

47
Q

Affects of Post-translational modifications of HTT

A
  • Post-translational modifications can affect mutant HTT misfolding, aggregation and toxicity in both directions (beneficial or deleterious)
  • Proteolytic cleavage –> More toxic
  • Phosphorylation (at S13, S16, S421) –> Less toxic
48
Q

Phosphorylation of HTT

A

decreases toxicity if occurs at residues: Serine13, Serine16, Serine421

49
Q

Proteolytic cleavage of HTT

A

proteolytic cleavage of HTT forms end fragments that are more toxic

50
Q

T/F: Serines 13 and 16 are critical determinants of HTT pathogenesis

A

TRUE (in animal models)
Transgenic mice expressing mutant HTT with serines 13 and 16 mutated to either aspartate (phosphomimetic) or alanine (phosphoresistant) were generated.

phosphomimetic = protective
phosphoresistant = toxic (can't be phosphorylated)
51
Q

T/F: Targeting huntingtin NT17 domain and its modifications might have therapeutic potential in HD

A

True because can potentially decrease toxicity through phosphorylation

52
Q

Effects of phosphorylation at S13 and S16 in mice

A

Phosphomimetic mice are protected from disease, including motor and psychiatric-like behavioural deficits and neurodegeneration.

53
Q

Pathogenic cellular mechanisms in HD: loss of function

A

Change in shape of HTT causes loss of function of:

  • Axonal Transport regulation
  • Transcriptional regulation of neural genes and BDNF
  • Anti-apoptotic functions
54
Q

Pathogenic cellular mechanisms in HD: gain of function

A

presence of elongated PolyQ stretch and subsequent misfolding leads to gain of function:
- proteolytic cleavage
- protein aggregation
- nuclear translocation (and aggregation in nucleus)
- dysregulated transcription
impairment of proteostasis network (incl. synaptic dysfunction, mitochondrial toxicity, axonal transport impairment)

55
Q

Gain of function: proteolytic cleavage

A

formation of toxic N-terminal fragments du

can also be made with aberrant mRNA splicing

56
Q

Gain of function: aggreagtion

A

formation of toxic oligomers and inclusion bodies in cells

Toxic forms can enter the nucleus and disrupt transcription

57
Q

Gain of function: in cytoplasm

A

Misfolded forms will impair the proteostatic network, causing:
- mitochondrial dysfunction and energy imbalance
- Synaptic dysfunction
- axonal transport impairment
NET result = neuronal death

58
Q

Best target for HD and why

A

HTT–because of domino effect

Prevent the need to target every individual dysfunction downstream (which is difficult)

59
Q

Effect on targeting 1 individual dysfunction

A

Ineffective on disease progression, with minimal overall benefit

60
Q

Most current therapies and those in clinical trials focus on

A

individual downstream effects of mutant HTT, rather than HTT itself

61
Q

Therapeutic targets in HD: mutant HTT

A
  • siRNA
  • antisense oligonucleotides
  • Agents that modulate HTT post-translational
    modifications (GM1, caspase inhibitors, etc.
62
Q

Therapeutic targets in HD: Preventing aggregation

A
  • chemical chaperones

- Heat Shock Protein response enhancers

63
Q

Therapeutic targets in HD: Prevent neurodegeneration

A

Stem cell transplantation

64
Q

Therapeutic targets in HD: Prevent symptoms

A
  • Tetrabenazine
  • Antipsycothics
  • Antidepressants
65
Q

Therapeutic targets in HD: Molecular and cellular dysfunctions

A
  • Excitotoxicity (memantine, riluzole)
  • Transcriptional dysregulation (Histone deacetylase inhibitors)
  • Apoptosis (Caspase inhibitors, Minocycline)
  • Mitochondrial dysfunction (CoenzymeQ10, Creatine)
  • Lack of BDNF (Encapsulated cells engineered to express BDNF )
  • Ganglioside metabolism (GM1)
66
Q

Symptoms of HD are due to:

A
  • neurodegeneration
  • molecular and cellular dysfunction that occurs prior to degen
    Treating the symptoms does not alter disease progression
67
Q

Stem cell treatment in HD

A

Used in an attempt to restore lost neurons
Clinical trials were initially promising BUT stem cells in striatum later subjected to HD problems (incl. degeneration)
Only provided temporary relief

PMCOL 412 (35 decks)

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