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Parkinson's Disease (Features (Symptoms (bradykinesia (suppression of…
Parkinson's Disease
Features
Symptoms
bradykinesia
(suppression of voluntary movement)
inherent inertia
(motor activity difficult to stop/start)
tremor at rest
muscle rigidity
(resistance to passive limb movement)
cognitive impairment
(at varying degrees)
commonly associated with dementia, depression and autonomic dysfunction
Mechanism
lack of dopamine
decreased activation of striatal D1+2 receptors
decreased inhibition of indirect pathway
decreased excitation of direct pathways
excessive activation of GPi-SNr complect
over inhibition of thalamocortical centre
Pathology
affects the basal ganglia
caudate
putamen
globus pallidus
subthalamic nuclei
substantia nigra
associated with
loss of DA neurons in substantia nigra
degeneration of nerve terminals in striatum
Cause
protein misfolding and aggregation
Lewy bodies
made from
a-synuclein
acting as a prion like protein?
a-synuclein normally exist is in a-helical structure
conformational change to B-sheet rich structure
structure polymerises to form toxic aggregates and amyloid plaques
hydrophobic residues usually hidden
now exposed causing proteins to stick to membrane
form more aggregates
normally highly expressed in brain
enriches at post-synaptic nerve terminals
synaptic vesicle recycling
dopamine neurotransmission
enhanced by
excitotoxicity
oxidative stress
inflammation
apoptosis
mitochondrial dysfunction
Genetic Mutations
Parkin
E3 Ubiquitin Ligase
Tags proteins for degradation
mutations are "loss of function"
improper targeting = toxic accumulation
UCH-L1
catalyses hydrolysis
involved in recycling ubiquitin ligases
dominant mutation
(193M)
identified in inherited PD
Polymorphism
(S18Y)
demonstrates UPS importance
DJ-1
a monitor of oxidative stress
LRRK2
encodes protein dardanin
Gain of function G2019S
increases kinase activity
interfere with cytoskeletal activity
vesicular trafficking disrupted
Animal Models
Genetic
a-synuclein model
overexpressing or expressing mutant variants
neurochemical deficits in nigrostriatal pathway
behavioural abnormalities
a-synuclein accumulation
Parkin
loss of function
quaking mouse model
myelin deficiency
tremor
behavioural deficits
Toxin
MPTP-based
show similar regional pattern of damage
but...
doesn't damage other monoaminergic neurons
lewy bodies not found
low dose treated monkeys show degeneration
putamen vs caudal
6-ODHA-based
mirrors PD symptoms
is selective for DA neurons
accumulates in cytosol
generates ROS
inactivates various molecules
Different injections sites
medial forebrain bundle
extensive DA depletion
substantia nigra pars compacta
more moderate DA depletion
more specific depletions
Treatments
Novel
Nature 13/04/17
3 DNA binding proteins + one small RNA
converted astrocytes into DA producing neurons
improved motor Symptoms of mice
Currently Used
Levodopa
a precursor of dopamine
normally prescribed with a decarboxylase inhibitor to
prevent peripheral side effects
in the periphery it prevents L-dopa being converted to dopamine
reduce dose required
decarboxylase can't cross BBB
L-dopa converted to dopamine in the brain
well absorbed from the small intestine
Short plasma half life of 2 hours
80% of patient see an improvement in motor symtpoms
gradual decline of efficacy
around 2 years into treatment
On/Off side effect develops
acute side effects
nausea
hypotension
hallucinations
dyskinesia
mAChR antagonists
mAChRs have an excitatory effect on striatal neurons
this is the opposite effect of DA
by suppressing the mAChR activity, helps to compensate for lack of DA.
eg. Benzotropine
A2A adenosine receptor antagonists
decreases receptor affinity for dopamine
enhances dopamines effects on neurons
side effects
inflammation
ischaemic damage
psychosis
insomnia