16 - PD 2 Flashcards
Parkin: what? works with?
E3 ubiquitin ligase. works with other ubiquitin activating and conjugating enzymes: targets proteins for proteosome destruction
if parkin doesn’t do its job what happens
failure of parkin mediated degradation of a synuclein may be a key factor leading to lewy bodies + DA neuronal death
PINK1: encodes what protein? which does what?
PTEN induced putative kinase 1 protein: protects cells from stress induced mitochondrial stress/oxidative stress
PINK1: structure? interacts with? so is associated with?
N terminal mitchon. localization sequence, transmembrane sequence, Ser/Thr domain, C terminal regulatory sequence. interacts with Parkin -associated with mitochondrial control systems.
PINK1: crucial role in?
recruiting Parkin to michondria to initiate autophagic destruction of damaged mitocohndria
DJ-1: aka? expressed where?
PARK7. widely expressed throughout CNS, in multiple cell types.
PARK7/DJ1 function
positive regulator of androgen receptor dependent transcription, redox sensitive chaperone, sensor for oxidative stress, protects against oxidative stress
PARK7 implicated in what? lower levels of DJ1 =?
many NDDs like PD, AD, ALS. lower DJ1 levels = DA neurons more susceptible to inflammatory mediated apoptosis.
neurotrophic factors: which ones change in PD?
BDNF and GDNF reduced: stimulate growth + survival of DA neurons.
3 animal models of PD
transgenic and knock out mice. injection of DA neuron specific toxins. injection of LPS.
what DA specific tonx?
MPTP and 6 OH dopamine: mediates direct killing of DA neurons
LPS injection?
PD mediated by inflammation, takes longer if injected systemically but faster when intracranial.
MPTP: what? binds to? effects?
synthetic opioid drug. binds strongly to DA transporter, taken up by DA neurons –> metabolized into toxic cation MPP+ and interferes with ETC in mitochondria.
common denominator of many NDDs?
inflammation
inflammation in PD: activate what? where in brain? results in? elevated levels of?
microglia: results in loss of DA neurons. more microglia in SN + striatum. elevated levels of pro-inflam. mediators like TNFa, ILs, ROS
nitrite: indicator for? levels?
indicator for NO free radicals: increased in CSF
inflammation: treatment for PD?
anti-inflammatory drugs/treatments can slow progress + lessen severity of PD
inflammation model of PD: initiate? inject what?
DA-neurodegeneration can be initiated by inflammogens, like LPS injection.
inhibitors of inflmmation protect against?
LPS, MPTP, 6OH DA induced DA neurodegeneration.
main in vitro model for studying PD pathogenesis?
primary rodent midbrain: then add LPS or MPTP, look at neurodegenration and inflammation
current treatment examples
DA agonists like L-DOPA. COMT inhibitors, MAO inhibitors. anticholinergics. DBS. anti inflammatory drugs. stem cell replacement.
problems with current treatment approaches
targeting, side effects, BBB, locus of action. relieve symptoms but don’t slow PD progression, eventually lose effectiveness
