Neuro - ALS Flashcards
What is ALS?
Motor neurone disease which effects both upper and lower MN
What does upper and lower MN damage lead too? Symptoms?
Denervation of the muscle, muscle wasting and weakness, split finger, tongue atropy and slurred speech
Onset?
Ranges from 30-60 years
Sporadic or familial?
90% sporadic with no family history
Is it progressive? Fatal in?
Yes and it is fatal in 3-5 years after onset
Is there a biomarker?
No and no specific test
How many genes have been found in the 10% familial forms? Which genes?
13 including SOD1 (superoxidase dismutase), TARBP, FUS, ANG and OPTN
Structural and functional MRIs of the brain show?
Changes in the shape and structure of the brain and changes in receptors and brain metabolism
Thinning of grey matter, white matter tract damage, changes in N-acetylasparate and myoinositol concentrations, reduced binding of sertonin 1A and many others
What is thought to cause ALS?
Glutamate excitotoxicity is thought to be one reason for the damage
Glutamate is the major excitatory neurotransmitter in the CNS and binds to NMDA and AMPA receptors on the post-synaptic membrane.
Excess activation of these receptors leads to neurodegeneration through the activation of calcium-dependent enzyme pathways which lead to oxidative stress and mitochondrial dysfunction. Can also result in the generation of free radicals which cause damage to intracellular organelles. The excess glutamate in the synaptic cleft may be due to excess release from the presynaptic neuron or reduced uptake into astrocytes
The mechanism for glutamate excitatory toxicity?
2 hypothesis - dying forward and dying back
Dying forward hypothesis?
Glutamate excitotoxicity causes the death of the upper MN first and these changes cause the death of the lower MNs
Dying back hypothesis?
Problem might not be the glutamate excitotoxicity but rather the lack of a neurotropic factor which causes the lower MN first and then the death of the upper MNs
What percentage of SOD1 mutations cause familial forms?
20%
What does the SOD1 mutation cause?
Gain of toxic function which induces conformational instabilty and misfolding of SOD1 leading to intracellular aggregates.
These aggregates inhibit normal proteosomal function and distrupt axonal transport systems. Also changes the handling of free radical and reactive oxygen species which can lead to cell injury and death
Overlap with FTDP17?
TDP-43 positive ubiquitinated cytoplasmic inclusions are found in almost all costs of ALS and more than 50% of patients with FTD
