Ageing of the nervous system Flashcards
What causes neurodegenerative disease?
We don’t know for sure but we suspect:
- Diet
- Exercise
- Smoking
- Alcohol (increase chance of getting dementia)
- Social activity
- Mental activity
(The rest all reduce chance of dementia)
What are some gene mutations that we know can cause certain neurodegenerative diseases?
- Mutations in APP cause Alzheimer’s.
- Mutations in α-synuclein cause Parkinson’s disease.
- Mutations in TDP-43 cause pre-frontal dementia
And certain repeats cause Huntington’s and Motor neuron disease (MND)
What is one neurodegenerative disease that is a “pure genetic disorder”?
Huntington’s Chorea:
its hereditary and Autosomal dominant.
What in particular causes Huntington’s disease?
And what is the relevance of this?
A trinucleotide repeat expansion.
The longer the repeat determines the status of the disease.
e.g. less than 28 CAG repeats and you wont get Huntington’s but more than 40 CAG reps then you’re guaranteed to get it.
In mice studies, did the mice without the gene still develop huntington’s?
No
Can the expression of the mutant gene induce disease in mice?
Yes
How does the expression of the mutant gene induce disease in mice?
- Inclusion bodies containing mHtt aggregates build
up selectively in vulnerable neurons – eventually in
the nucleus. - Aggregates can interact with transcription factors
and modulate gene expression. - Cell death follows – but mechanism not clear: So we know the cause of it in some patients but not all.
What is MND/ ALS?
What is the age of onset usually?
- Excessive loss of motor neurones in the spinal cord, brainstem, and/or
motor cortex. - Age of onset typically 50-60, with life expectancy 5 years after onset
What causes MND/ALS?
- A hexanucleotide repeat recently identified in C9ORF72.
• The same gene defects account for ~ 15% of the sporadic disease with
C9ORF72 being most common.
- SOD1 and TDP-43 can form toxic protein aggregates.
- The hexanucleotide repeat (up to 20kb) forms nuclear inclusions and can generate toxic peptides.
Using MND as an example describe the progressive symptoms of neurodegeneration.
- A motor neuron will innervate many muscle fibres – this is the
motor unit - If a motor neuron dies, other near by ones take over the territory by a process called compensatory sprouting, and this increases the size of the motor unit.
- However, capacity to do this is limited and motor units are eventually lost.
- The disease state is characterised by the excessive loss of motor
units and severe muscle atrophy. - The Important point is that in all disease states a considerable amount of damage is done before symptoms become apparent.
Summarise common and Unique Features in neurodegenerative disease
(1) Protein aggregation is common, but protein species is unique.
e. g. (TDP-43 protein aggregates in motor neurons in ALS Synuclein aggregates in dopaminergic neurons in Parkinson’s disease)
(2) Importantly, once initiated all of these diseases can be:-
- masked by compensatory sprouting
- exacerbated by activation of microglia and astrocytes and/or loss
of trophic support - “spread” through the nervous system in a characteristic manner
How do protein aggregates form aka the prion hypothesis.
(1) Protein can exist in at least 2 states
(2) One state is prone to aggregation
(3) Disease mutation increases probability
(4) Nucleation and propagation
How do protein aggregates spread from one cell to the next?
- Firstly, one cell could release the protein
by direct secretion, membrane penetration or during cell death. - The misfolded protein could be released in exosomes, these
could then fuse with the membranes of neighbouring cells. - The proteins could travel between cells in tunnelling nanotubes.
- The proteins could be internalised by micropinocytosis or
receptor-mediated endocytosis. - The proteins could escape from endocytosed vesicles.
- The protein within the cell may lead to more seeding and fragmentation by replication machinery.
How might you mitigate against the disease and/or limit damage?
- Replacement therapy
• L-dopa for Parkinson’s disease
• Cholinesterase inhibitors for Alzheimer’s - Excitotoxicity
• glutamate receptor antagonists (AMPA, NMDA)
• Na channel antagonists
• Voltage gated-calcium channel antagonists - Accumulation of toxic proteins
• β and γ secretase inhibitors to prevent generation of toxic Aβ peptides
• Immunisation strategies to remove toxic Aβ peptides and other toxic
aggregates (e.g. Tau and synuclein) - Trophic support
• NGF, BDNF, GDF, VEGF to support neurons - Anti-inflammatory drugs
• COX1/2 inhibitors
What is the effect of exercise on the aging nervous system?
• Exercise stresses the muscles and causes the production of growth hormones that positively affect the
brain.
- Exercise improves the blood flow to the brain, helping to keep it healthy.
- Complete lack of movement decreases the numbers of neural stem cells in the brain by 70%.
- Inactivity reduces the growth of neurons, reducing our ability to learn and move.
