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- Clinical Introduction
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1. Frontotemporal dementia
- Prof. Bruce Miller
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2. Parkinson disease
- Prof. Stanley Fahn
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3. Atypical parkinsonian syndromes
- Dr. David Burn
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4. Huntington's disease
- Prof. Roger Barker
- Neuroimaging
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5. Molecular brain imaging (PET) in diseases with dementia
- Prof. Karl Herholz
- Pathology, Genetic and Molecular Aspects (1)
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6. A molecular understanding of Alzheimer's disease
- Prof. John Hardy
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7. Neuropathology of neurodegenerative disorders
- Prof. Jillian Kril
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9. Ubiquitination and Alzheimer related disorders
- Prof. John Mayer
- Pathology, Genetic and Molecular Aspects (2)
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10. The molecular biology of Huntington's disease
- Prof. David C. Rubinsztein
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11. Metals, oxidative stress and neurodegeneration
- Prof. Ashley Bush
- Latest Developments in the Field
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12. Animal models of tauopathy
- Prof. David Westaway
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13. Parkinson's disease and transplants
- Prof. Roger Barker
- Archived Lectures *These may not cover the latest advances in the field
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14. Neuropathology of neurodegenerative disorders
- Prof. Jillian Kril
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15. Motor neurone disease: molecular basis
- Prof. Kevin Talbot
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16. Alzheimer's disease (AD)
- Prof. John Hodges
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17. Frontotemporal dementia syndromes
- Prof. John Hodges
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18. Motor neurone disease: clinical aspects
- Prof. Kevin Talbot
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19. Neuro-imaging in dementia: using MRI in routine work-up
- Prof. Philip Scheltens
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20. Prion diseases
- Prof. Pierluigi Gambetti
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21. Mitochondrial disorders and neurodegeneration
- Prof. Anthony Schapira
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23. Mutations in parkinsonian syndromes
- Dr. Andrew Singleton
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25. Frontotemporal dementia
- Prof. Bruce Miller
Printable Handouts
Navigable Slide Index
- Intro slide
- Huntington's disease
- Pathology
- The Huntington disease gene
- Anticipation
- Why is there anticipation?
- Incomplete penetrance
- How does mutation cause disease?
- Multiple pathways to disease
- Selected possible mechanisms
- Aggregates in HD
- Aggregates in other diseases
- Aggregates formation in various models
- Poly (Q) length and time dependent aggregation
- Relationship between aggregation and cell death
- More complex relationship
- The roles of aggregates in HD in related disorders
- Transcription (1)
- Transcription (2)
- Transcription (3)
- CBP functions
- ROS and HD
- ROS in cell models in HD
- Cell death in several experiments
- Treating HD with antioxidants
- Therapeutic pathways
- Proteasome
- Autophagy pathway
- Rapamycin reduces aggregation and cell death
- In vivo model
- HD transgenic mice model (1)
- HD transgenic mice model (2)
- HD transgenic mice model (3)
- Conclusions
Topics Covered
- Clinical presentations of HD
- Pathological features
- Genetic basis
- Trinucleotide repeat expansion mutation
- Huntingtin protein and cell damage
- Abnormal protein aggregation
- Transcriptional abnormalities
- Raised levels of reactive oxygen species
- Future directions for therapeutic intervention
- siRNA approaches
- Induction of autophagy
- Update interview: Clinical presentations of HD
- Update interview: Pathological features
- Update interview: Genetic basis
- Update interview: Trinucleotide repeat expansion mutation
- Update interview: Future directions for therapeutic intervention
- Update interview: RNAi approaches
- Update interview: Induction of autophagy
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Rubinsztein, D.C. (2020, May 22). The molecular biology of Huntington's disease [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 5, 2024, from https://doi.org/10.69645/KDCP4326.Export Citation (RIS)
Publication History
Financial Disclosures
- No conflicts of interest for this talk.
Update Available
The speaker addresses developments since the publication of the original talk. We recommend listening to the associated update as well as the lecture.
- Full lecture Duration: 46:11 min
- Update Interview Duration: 10:13 min
A selection of talks on Neurology
Transcript
Please wait while the transcript is being prepared...
0:03
Huntington's disease is a devastating
disorder, some of a more dominant
neurodegenerative disease, that typically
presents with the triad of symptoms.
These include abnormal movements,
particularly chorea,
as you can see in the slide.
But perhaps more devastating to the family
and to the patients are the psychiatric
disturbances, and cognitive deterioration
that characterize this disorder.
Huntington's disease can
present at any age, however,
the median age at onset
is around 40 years.
This results in many cases of Huntington's
disease presenting with symptoms or
signs after they've already had children.
0:39
Huntington's patients typically die
about 15 years after disease onset.
The analysis of postmortem brains
has provided important insights into
the regional specificity of
the Huntington mutations effects.
The top brain in the slide represents
a normal sample, while the bottom brain
represents a sample from a Huntington's
patient at the end stages of the disease.
The CNP in the top panel
represent the caudate and putamen.
If you look at the Huntington's brain,
you can see that these regions are almost
completely absent, and
there's also significant cortical atrophy.
Indeed, loss of cells from the caudate and
putamen, and
from the cortex represent fairly
early events in the disease course.
1:23
The gene causing Huntington's
disease was identified in 1993,
by a large consortium headed
up by Jim Gazelle at Harvard.
The Huntington's disease gene
encodes a very large protein of
more than 3000 amino acids, and
this protein is called huntingtin.
The Huntington's mutation causes
changes close to the amino
terminus of this protein.
The coding region in the gene
at this position comprises
a series of uninterrupted
CAG trinucleotide repeats.
So the sequence reads CAG,
CAG, CAG, CAG, CAG etc.
Normal individuals have 35 or
fewer of these uninterrupted CAGs,
while diseases are associated with 36 or
more of these repeats.
Each of these CAG repeats
represents the codon for
the amino acids glutamine, so
the mutant protein has a very long and
abnormally expanded polyglutamine stretch.