Parkinsons Disease Flashcards
toxic/environmental factors
rural living, drinking well water, and exposure to heavy metals, hydrocarbons, pesticides, and/or herbicides
early onset vs. late onset
early onset most likely due to genetics
late onset implies cumulative exposure to putative toxins, CNS aging, and other cell death mechanisms
How do the neurotoxins affect dopamine?
MPTP is converted to MPP+ which causes the destruction of dopamine neurons
PINK1 genetic mutation
produces alterned PTEN induced putative kinase 1 which results in mitochondrial dysfunction
PRKN genetic mutation
produces altered protein Parkin resulting in proteosomal dysfunction
LRRK2 gene mutation
produces altered protein dardarin resulting in altered protein-protein interactions (late-onset)
SNCA gene alteration
produces misfolded alpha-synuclein causing aggregation and formation of Lewy bodies (early onset)
GBA gene alteration
produces altered protein glucocerobosidase resulting in alterations in lysosomal function and decreased clearance of misfolded proteins
various PD pathogenic mechanisms
abnormal apoptosis/autophagy, excitotoxicity, inflammation, nitric oxide toxicity, and oxyradicals
Hallmark change
loss of dopamine projections from the Substantia Nigra to the striatum
Presence of Lewy bodies in various of the brain
- activation of TLR1/2 on microglia results in activation of the inflammasome causing release of inflammatory cytokines; involved in protein misfolding and altered autophagy
- alpha-synuclein stimulates NO synthase causing DNA damage and activation of PARP-1 leading to PAR-induced cell death
PAR
PAR normally repairs DNA
in parkinsons it also binds with preformed fibrils (PFF) contributing to additional alpha-synuclein misfolding
D1 pathway
direct pathway
D2 pathway
indirect pathway
What percentage of neuron loss before clinical manifestations are seen?
70-80%
