neurodegeneration Flashcards
Parkinson's disease neuropathology: Identify the dopaminergic pathway in the brain which degenerates and how the loss of dopamine triggers the motor clinical symptoms; and explain which other neuronal pathways are affected in Parkinson’s and what is the underlying pathological process
synthesis of dopamine, including enzymes, in pre-synaptic nerve terminal
tyrosine -> DOPA (via tyrosine hydroxylase - rate-limiting step) -> dopamine (via DOPA decarboxylase)
how is dopamine removed from synaptic cleft (back into pre-synaptic neurone, or into glial cell)
via dopamine transporter (DAT) or noradrenaline transporter (NET)
3 enzymes which metabolise dopamine (remove by degradation)
MAO-A (expressed on mitochondrial membranes of pre-synaptic neurone and glial cells; also metabolises noradrenaline and serotonin), MAO-B (expressed on mitochondrial membranes of pre-synaptic neurone; only metabolises dopamine), COMT (wide distribution e.g. in glial cells and post-synaptic cell, and metabolises all catecholamines)
4 major locations of dopaminergic pathways
nigrostriatal pathway (most important pathway for Parkinson’s disease), mesolimbic pathway (associated with Schizophrenia), mesocortical pathway (associated with Schizophrenia), tuberoinfundibular pathway
describe nigrostriatal pathway, and what inhibition causes
cell bodies in susbstantia nigra pars compacta (SNc), with axons projecting to striatum; inhibition results in movement disorders
describe mesolimbic pathway
cell bodies in VTA (ventral tegmental area), with axons projecting to NAcc (nucleus accumbens) as brain reward pathway
what is activation of mesolimbic pathway associated with
positive schizophrenia symptoms
describe mesocortical pathway and importance
cell bodies in VTA (ventral tegmental area), with axons projecting to cerebrum; important in executive functions and complex behavioural patterns
what is inhibition of mesocortical pathway associated with
negative schizophrenia symptoms
describe tuberoinfundibular pathway, and what inhibition causes
cell bodies in arcuate nucleus, with axons projecting to median eminence; inhibition results in hyperprolactinaemia, so accounts for side effects seen if dopaminergic pathways targeted
describe pathophysiology of Parkinson’s disease
severe loss of dopaminergic projection cells in substantia nigra pars compacta (SNc), causing degeneration of nigrostriatal tract
what are found within neuronal cell bodies in Parkinson’s disease
Lewy bodies
what are found within axons in Parkinson’s disease
neurites
what do Lewy bodies and neurites consist of in Parkinson’s disease
abnormally phosphorylated neurofilaments ubiquitin and a-synuclein (not targeted in treatment)
