parkinsons Flashcards
what are symptoms of parkinsons disease
main symptoms:
akinesia/bradykinesia
muscle rigidity
resting tremor
additional features:
loss of postural reflexes, depression
what causes pd
loss of nigrostriatal DA neurones leads to a corresponding loss of DA in caudate/putamen
remaining neurones show lewy body inclusions containing aggregated alpha synuclein
additional cell loss in locus coeruleus and nucleus basalis
describe the synthesis of dopamine
tyrosine is converted to LDOPA by Tyrosine hydroxylase which is converted to dopamine by AADC
describe the genetics of PD
sporadic PD does not show mendelian inheritance
but over 15 genes responsible for familial forms have been identified, such as mutations in SCNA1 which codes for alpha synuclein and PRKN which codes for parkin which is the most common cause of juvenile PD
describe autosomal recessive pd
PARK2 mutation:
juveline (early 20s)
on PRKN gene on chromosome 6
mutations cause loss of function and failure of this form of protein degredation
parkin is a E2 ubiquitinprotein ligase
normally targets alpha synuclein and targets it for proteasomal decay
heterozygotes for parkin mutations is a risk factor for late onset parkinsons
PARK6:
mutations in gene PINK-1, a kinase which targets mitochondria, causes early a recessive onset parkinson like syndrome
PINK1 binds to phosphorylates PARKIN
mutant parkin/pink1 inhibits the mitophagy of damaged mitochondria
parkin/pink1 promote mitophagy of damaged mitochondria and maintain neurone health
describe the genetics of autosomal dominant pd
PARK1 mutation:
early adult onset (40s)
rapid progression, associated with lewy bodies in S. nigra
mis-sense mutations in alpha synuclein on chromosome 4
aggregation of a-synuclein occurs
PARK4:
genomic triplication of normal a-synuclein leads to 4 functional copies, leads to early onset PD
how might pd be induced
post encephalitis
drug induced (MPTP)
neurotoxin induced such as pesticide rotenone
CO poisoning
traumatic injury, stroke
what disease is linked to PD
gauchers disease is recessive, caused by mutations in gene GBA, heterozygotes have increased risk of PD
does oxidative stress cause PD
rotenone and MPTP inhibit mitochondrial complex 1
a SNP in NADH dehydrogenase (part of complex 2) results in a reduced risk of sporadic PD
oxidative stress may cause PD
antioxidant therapy not effective in slowing PD
is there a neuroinflammatory component to parkinsons
TNF is elevated in CSF of pd patients
activation of microglia has been shown in PD
chronic use of non steroidal anti inflammatory drugs lowers risk for development of PD in humans by 46%
why are s nigra neurones particularly susceptible
s nigra neurones have pacemaker activity and rely in part on L type calcium channel Cav1.3 as it has a medium low threshold current, therefore has continuous ca entry and may be more susceptible due to a defect in ca handling
production of dopamine and its metabolism may lead to oxidative stress
mitochondrial dysfunction leads to disrupted ca sequestration
how may animals be used as models for pd
reserpine treatment: blocks VMAT, depletes stored DA and NA, reversed by LDOPA
a 6-OH dopamine s nigral injection in rats
transgenic over expressino of a synuclein in mice and drosophila
what is the 6-OHDA model of pd
unilateral lesion of s.nigra
causes turning behaviour
reliable measure of denervation and supersensitivity of DA receptors
there are compensatory changes and so not a model of progressive disease
good model for testing potential treatments
how does MPTP affect neurones
MPTP is a product of opioid narcotic synthesis
it is a substrate for MAO and creates a pyridinium ion (MPP+)
mpp+ taken up by dopamine transporter, then inhibits complex 1 in mitochondira which leads to oxadative stress, effectiveness depends on species
how is MPTP used to model pd
there is an increase in lipid peroxidation decrease in number of s nigra neurones decrease in striatal da responds to drug therapy used in pd shows no progression
