ALS - Pathophysiology Flashcards
Where are UMN and LMN located?
UMN in brain
LMN in spinal cord
What does UMN pathology cause?
Spasticity and mild weakness
What does LMN pathology cause?
Makor weakness and wasting
Which glutamate transporter is lost in ALS?
EAAT2
How is EAAT2 function lost in ALS?
Turned off by mSOD1
What does abnormal glutamate handling lead to?
Over excitation of neurons and death
Excitotoxicity
Outline the protein pathology in ALS
Mutated/damaged proteins accumulate in the cell
Associated with reduction in axonal length and cellular toxicity
Which growth factor may be useful in ALS?
VEGF
How do we know that VEGF is relevant to ALS?
Targeted deletion in models causes ALS pathology
Overexpression or external delivery of VEGF delays the progression of disease
Why is there increased oxidative damaged with mSOD1?
mSOD1 catalyses the breakdown of hydrogen peroxide to peroxynitrite
What effect does peroxynitrite have on cells?
Nitration of the tyrosine residue which kills cells
How is axonal transport affected in ALS?
Abnormal accumulation of neurofilaments in the soma/axons of MNs
How do we know neurofilaments have a role in ALS?
Mice with overexpression of neurofilaments display MN dysfunction and some MND symptoms
How do astrocytes add to the pathology of ALS?
Astrocytic inclusions surround the nucleus and secrete factors toxic to MNs (like TNF alpha)
How is excitotoxicity involved in ALS?
Causes EAAT2 loss so less glutamate clearance from the synapse
Glutamate then interacts with extrasynaptic NMDAR
