HD I Flashcards
HD is a genetic neurodegenerative disorder characterized by:
- motor symptoms
- behavioral and psychiatric disturbances
- cognitive dysfunction
Prevalence of ______ in Caucasian populations
1 in 10000
rare but most common genetic neurodegenerative disease
2 types based on age of onset
Age of symptoms onset:
- Adult form: 35-45 years
- Juvenile form: <20 years (~10% of HD cases)
Average age of onset for adult HD
35-45 years
Age of onset for junvenile form
<20 years
Time from onset to death
Inexorably progressive: death 15-20 years after onset
Hallmarks of HD
progressive motor symptomatology
different b/t adult and juvenile HD
Motor Symptomology seen in adult onset HD
involuntary choreic movements, impaired co-ordination
of voluntary movements affecting gait, speech and swallowing.
Motor Symptomology seen in juvenile HD
bradykinesia, rigidity, dystonia, epileptic seizures
chorea is often ABSENT
Non-motor features of HD
- 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
Cognitive dysfunction (meaning)
learning impairment, reduced ability to plan and organize, difficulty concentrating on tasks
Behavioural and psychiatric disturbances (meaning)
change in personality, depression, increased tendency to commit suicide, psychoses and schizophrenia in 10% of patients
Clinical features of HD
- Motor symptoms (differ b/t adult and juvenile HD)
- Cognitive dysfunction
- Behavioural and psychiatric disturbances
T/F: All symptoms progress at the same rate
FALSE
progression if different symptoms over the disease course
Chorea
‘dance’ in ancient greek
movement resembles a dance
HD neuropathology–areas affected
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
Atrophy of ____ starts early on in prodromal HD patients
White matter
HD brain would show atropy of….
white, grey matter and striatum
further areas: cortex, cerebellar Purkinje cells, globus pallidus
In HD, the selective dysfunction of ____ neurons progresses to the degeneration of these neurons
striatal
In adult onset HD, loss of _______ ) in the striatum determine disruption of the _____, ____ firing of thalamo-cortical neurons and overall _____ movement
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)
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
Enk+ (D2R-expressing) and SP+ neurons (D1R-expressing); decrease; rigidity
Why is chorea not present in juvenile HD
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
Early adult HD
chorea and dyskinesia
D2R-expressing neurons lost
Late Adult HD
Bradykinesia and rigity
Both D1R and D2R-expressing neurons lost
HD is due to an _______ mutation in the___ gene,
which codes for a protein named _____
autosomal dominant; HD; huntingtin (HTT)
Normal HD gene has ___ ____ repeats
<36 CAG repeats
Adult-onset HD gene has ___ ___ repeats
36-55 CAG repeats
Junvenilt HD gene has ___ ___ repeats
56-120 CAG repeats
CAG protein repeats determine the length of ____ and proteins containing extended ___ are ___ to neurons and associated with ____
PolyQ; PolyQ; toxic; neurodegeneration
Why are more CAG repeats bad
Because more CAG = longer PolyQ and polyQ containing proteins are toxic to neurons and cause neurodegeneration
of polyQ in different Disease states (non-HD, adult-onset and juvenile)
Non-HD: <36 Q
Incomplete penetrance: 36-39 Q
Adult-onset: 36-55 Q
Juvenile: 56-120 Q
T/F: A predictive genetic test can establish the number of CAG repeats inherited
True
In normal HD # of Qs
normally 36 CAG repeats in the coding region (1st exon)
Translated into polyglutamine (polyQ) in huntingtin protein
Relationship between # of CAG repeats and HD onset
more CAG repeats (and therefore longer PolyQ) = earlier onset
T/F: all cases of HD are genetic
TRUE
What is Huntingtin (HTT)
- 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
What factors can influence HTT movement into the nucleus
stress–incl. heat, lack of neurotrophic factors
HTT is a ___ protein involved in…
Scaffold protein involved in: • Vesicle trafficking • Axonal transport • Transcriptional regulation • Stress responses • Autophagy • Regulation of apoptosis (anti-apoptotic) • DNA damage responses
T/F: HD is caused by both the loss of normal
huntingtin functions and the newly acquired
toxicity of mutant huntingtin (gain-of-function)
TRUE
Normal functions that are lost
- Axonal Transport regulation
- Transcriptional regulation of neural genes and BDNF
- Anti-apoptotic functions
How are normal functions affected
Loss normal function of HTT due to aberrant conformation/interactions
How are toxic functions gained
They result from the expanded polyQ region
Gained TOXIC functions include:
Formation of protein aggregates
- Impaired Mitochondrial metabolism
- Exitotoxicity
- Trascriptional dysregulation
- Aberrant cell signaling
- Impaired synthesis of gangliosides
How does increased PolyQ change the conformation of HTT
Expanded polyQ stretches tend to misfold and to undergo a process of fibrillation and aggregation
T/F: aggregates of mutant HTT can have a beneficial role
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
Most toxic forms of Mutant HTT
monomeric form or oligomers of the mutant protein
Affects of Post-translational modifications of HTT
- 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
Phosphorylation of HTT
decreases toxicity if occurs at residues: Serine13, Serine16, Serine421
Proteolytic cleavage of HTT
proteolytic cleavage of HTT forms end fragments that are more toxic
T/F: Serines 13 and 16 are critical determinants of HTT pathogenesis
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)
T/F: Targeting huntingtin NT17 domain and its modifications might have therapeutic potential in HD
True because can potentially decrease toxicity through phosphorylation
Effects of phosphorylation at S13 and S16 in mice
Phosphomimetic mice are protected from disease, including motor and psychiatric-like behavioural deficits and neurodegeneration.
Pathogenic cellular mechanisms in HD: loss of function
Change in shape of HTT causes loss of function of:
- Axonal Transport regulation
- Transcriptional regulation of neural genes and BDNF
- Anti-apoptotic functions
Pathogenic cellular mechanisms in HD: gain of function
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)
Gain of function: proteolytic cleavage
formation of toxic N-terminal fragments du
can also be made with aberrant mRNA splicing
Gain of function: aggreagtion
formation of toxic oligomers and inclusion bodies in cells
Toxic forms can enter the nucleus and disrupt transcription
Gain of function: in cytoplasm
Misfolded forms will impair the proteostatic network, causing:
- mitochondrial dysfunction and energy imbalance
- Synaptic dysfunction
- axonal transport impairment
NET result = neuronal death
Best target for HD and why
HTT–because of domino effect
Prevent the need to target every individual dysfunction downstream (which is difficult)
Effect on targeting 1 individual dysfunction
Ineffective on disease progression, with minimal overall benefit
Most current therapies and those in clinical trials focus on
individual downstream effects of mutant HTT, rather than HTT itself
Therapeutic targets in HD: mutant HTT
- siRNA
- antisense oligonucleotides
- Agents that modulate HTT post-translational
modifications (GM1, caspase inhibitors, etc.
Therapeutic targets in HD: Preventing aggregation
- chemical chaperones
- Heat Shock Protein response enhancers
Therapeutic targets in HD: Prevent neurodegeneration
Stem cell transplantation
Therapeutic targets in HD: Prevent symptoms
- Tetrabenazine
- Antipsycothics
- Antidepressants
Therapeutic targets in HD: Molecular and cellular dysfunctions
- 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)
Symptoms of HD are due to:
- neurodegeneration
- molecular and cellular dysfunction that occurs prior to degen
Treating the symptoms does not alter disease progression
Stem cell treatment in HD
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
