Parkinsons Flashcards
Who to quote for toxin base model reviews?
Bove et al 2005
Blesa et al 2012
Dauer et al 2003
Talk about 6-OHDA
1st model with substania nigra pars compacta dopamine cell death
Induced toxicity selective for dopaminergic neurons as theres preferential uptake by dopamine transporter
No clear mechanism of cell death and no LB
Talk about MPTP
analogue of meperidine is MPTP and it was found in drug users 1980s
Talk about paraquat
herbicide inducing PD and is similar to MPP+, doest cross the BBB very easily
Talk about rotenone
Binds to the same site as MPP and blocks complex I
Who talks about rotenone and paraquat?
Tanner et al 2011- link with parkinsons disease in farmers
Why are genetic based models of parkinsons studies despite only 5% being familial?
Similar pathogenic process in both genetic and sporadic forms of PD
What is the commonest mutation found in familial PD?
LRRK-2 , correlation between VPS35 mutations and increased LRRK-2 kinase activity - dundee lends evidence to the common signalling pathway between proteins implicated in PD
Definition of PD
neurodegenerative condition resulting from the loss of dopaminergic neurones forming the nigrostriatal pathway causing characteristic symptoms of rigidity, bradykinesia, and postural instability
definition of basal ganglia
collection of sub cortical nuclei consisting of caudate, putamen, subthalamic nucleus, substatntia nigra, globus pallidus and thalamus
Define lewy bodies
intracellular proteinaceous cytoplasmic inclusions with a desne protein core and peripheral halo containing ubiquitin and neurofilament proteins , the key component being alpha synuclein
what are some other neuronal losses in PD?
noradrenergic neurons- locus coerulus
serotonergic neurons- raphe nucleus
cholinergic neurons- dorsal motor nucleus of vagus
Define alpha synuclein
natively unfolded structure with great synaptic plasticity and aggregation will form insoluble filaments— fibrillar forms found in LB
high concentrations are present in pre-synaptic terminals and it has a role in vesicular recycling and dopamine transmission
What gives rise to sporadic PD?
result of interaction between environmental exposure to toxins, natural ageing process of cells and finally genetic predisposition
What does Parkin do?
the parkin gene encodes for E3 ligase which is a key enzyme that tags proteins meant for degradation with ubiquitin and is part of the ubiquitin proteosome system
mutation results in loss of function and toxic accumulation of proteins
What was the first gene linked to PD?
SNCA in 1997 which codes for alpha synuclein and polymeropoulos 1996— identified 4q21 -q23 were found to be linked to the PD phenotype in a large kindred with autosomal
dominant PD, - italian family
What does UCH-L1 do?
hydrolyses C-terminal ubiquitin esters and is involved in recycling ubiquitin ligated to misfolded proteins
mutation - familial PD
What does DJ-1 do?
localised to mitochondria and may be important in mitochondrial function+ protection against reactive oxygen species
What does LRRK2 gene do?
encodes dardarin
gain of function results in increased kinase activity which interferes a/b tubulin which is needed for cytoskeleton mobility and vesicular trafficking
describe the cell death in PD
markedly increased in PD with increase in Bax positive Substantia nigra pars compacta dopamine neurons
therapeutics for PD?
1st line is levodopa co-administered with dopa-decarboxylase which inhibits peripheral conversion and side effects
selegiline- ,monoamine oxidase inhibitor- it breaks down dopamine and the selegiline will prevent this
dopamine agonists- bromocriptine, apomorphine
What are adenosine a2 receptor antagonists?
the GABA-ergic striatal pallidal neurons that express dopamine receptors(D2) also express adenosine A2a receptors. Activation of these A2-a receptors opposes the effects of the D2-receptors by decreasing affinity for dopamine and activates the signalling cascades that dopamine inhibit
Talk about gene therapy in PD
GAD(glutamate decarboxylase is the key enzyme that synthesizes GABA, producing GABA in the STN will inhibit STN activity and decrease thalamic inhibition
bilateral delivery of AAV2-GAD in the subthalamic nucleus
