Translational research with animal models
for Huntington’s disease (Prof. Bertoglio)
1. Huntington’s Disease
What Causes Huntington's?
o HD is caused by a CAG-repeat expansion in the HT-gene.
Normal HTT Gene: < 35 CAG-repeats
Mutant HTT (mHTT): ≥ 36 CAG-repeats
The more repeats, the earlier and more severe the
disease.
What happens during a CAG-expansion?
o The CAG-repeat codes for the amino acid glutamine (Q) too many
repeats an overly long polyglutamine (polyQ) tract in the
huntingtin protein.
o This leads to:
Misfolding of the protein
Aggregates (clumping) of mHTT
Disruption of cellular processes
Ultimately: neurodegeneration
Mainly loss of neurons in the striatum the brain shrinks
(atrophy).
Risk dependent on Repeat Count
o 27-35: 0% likelihood of developing disease phenotype
o 36-39: higher likelihood of developing phenotype
o 40-55: 100% likelihood of developing phenotype
o > 56: probably early onset and severe progressive phenotype
More repeats more severe and earlier onset of the disease.
Therapeutic Options: Why Lower ?
o The bottom slide shows 3
options for tackling huntingtin:
(1) Mutant huntingtin
lowering (mHTT
lowering) — Effective
Research shows
that lowering
mutant HTT:
o Reduces
neurodegeneration
o Can delay symptoms
This is currently the main therapeutic
strategy.
(2) Completely silencing huntingtin — Dangerous
HTT is necessary for:
o Neuronal survival
o Axonal transport
o Embryonic development
Complete HTT-inactivation is harmful (deleterious).
(3) HTT modulation — Unknown effect
HTT Modulation = subtly modifying function.
However:
1
, o Insufficient knowledge
o Unpredictable effects
Disease progression
o Screening of people carrying the expansion follow up in the clinic
o 45 years is disease of onset
In the years before the official diagnosis Chorea: loss of balance, …
o Cognitive deficits: more memory problems, changes in the mood…
o Finally motor impairment rigidity…
From the therapeutic perspective no disease modifying treatments
o The last decays large number of promising strategies
1.1. HD-integrated staging system
Example of post mortem tissue → ventricle is enlarged … → neurodegeneration
Stage 1: based on MRI scans → detect changes of volume
Stage 2: some motor deficits observed by a doctor
Stage 3: patient becomes less and less independent
Changes in volume: neurons in structure are already dead → looking at quite advanced
pathologic processes
1.2. Pathogenic pathways in HD
Everything is downstream of the expression of the Huntington gene
Fragment is reactive → translocated into nucleus → start aggregate, and can interact with several
components and cause dysregulation of transcription of several proteins/factors
2
for Huntington’s disease (Prof. Bertoglio)
1. Huntington’s Disease
What Causes Huntington's?
o HD is caused by a CAG-repeat expansion in the HT-gene.
Normal HTT Gene: < 35 CAG-repeats
Mutant HTT (mHTT): ≥ 36 CAG-repeats
The more repeats, the earlier and more severe the
disease.
What happens during a CAG-expansion?
o The CAG-repeat codes for the amino acid glutamine (Q) too many
repeats an overly long polyglutamine (polyQ) tract in the
huntingtin protein.
o This leads to:
Misfolding of the protein
Aggregates (clumping) of mHTT
Disruption of cellular processes
Ultimately: neurodegeneration
Mainly loss of neurons in the striatum the brain shrinks
(atrophy).
Risk dependent on Repeat Count
o 27-35: 0% likelihood of developing disease phenotype
o 36-39: higher likelihood of developing phenotype
o 40-55: 100% likelihood of developing phenotype
o > 56: probably early onset and severe progressive phenotype
More repeats more severe and earlier onset of the disease.
Therapeutic Options: Why Lower ?
o The bottom slide shows 3
options for tackling huntingtin:
(1) Mutant huntingtin
lowering (mHTT
lowering) — Effective
Research shows
that lowering
mutant HTT:
o Reduces
neurodegeneration
o Can delay symptoms
This is currently the main therapeutic
strategy.
(2) Completely silencing huntingtin — Dangerous
HTT is necessary for:
o Neuronal survival
o Axonal transport
o Embryonic development
Complete HTT-inactivation is harmful (deleterious).
(3) HTT modulation — Unknown effect
HTT Modulation = subtly modifying function.
However:
1
, o Insufficient knowledge
o Unpredictable effects
Disease progression
o Screening of people carrying the expansion follow up in the clinic
o 45 years is disease of onset
In the years before the official diagnosis Chorea: loss of balance, …
o Cognitive deficits: more memory problems, changes in the mood…
o Finally motor impairment rigidity…
From the therapeutic perspective no disease modifying treatments
o The last decays large number of promising strategies
1.1. HD-integrated staging system
Example of post mortem tissue → ventricle is enlarged … → neurodegeneration
Stage 1: based on MRI scans → detect changes of volume
Stage 2: some motor deficits observed by a doctor
Stage 3: patient becomes less and less independent
Changes in volume: neurons in structure are already dead → looking at quite advanced
pathologic processes
1.2. Pathogenic pathways in HD
Everything is downstream of the expression of the Huntington gene
Fragment is reactive → translocated into nucleus → start aggregate, and can interact with several
components and cause dysregulation of transcription of several proteins/factors
2
