16 - PD 2

Question 1

Parkin: what? works with?

Answer 1

E3 ubiquitin ligase. works with other ubiquitin activating and conjugating enzymes: targets proteins for proteosome destruction

Question 2

if parkin doesn’t do its job what happens

Answer 2

failure of parkin mediated degradation of a synuclein may be a key factor leading to lewy bodies + DA neuronal death

Question 3

PINK1: encodes what protein? which does what?

Answer 3

PTEN induced putative kinase 1 protein: protects cells from stress induced mitochondrial stress/oxidative stress

Question 4

PINK1: structure? interacts with? so is associated with?

Answer 4

N terminal mitchon. localization sequence, transmembrane sequence, Ser/Thr domain, C terminal regulatory sequence. interacts with Parkin -associated with mitochondrial control systems.

Question 5

PINK1: crucial role in?

Answer 5

recruiting Parkin to michondria to initiate autophagic destruction of damaged mitocohndria

Question 6

DJ-1: aka? expressed where?

Answer 6

PARK7. widely expressed throughout CNS, in multiple cell types.

Question 7

PARK7/DJ1 function

Answer 7

positive regulator of androgen receptor dependent transcription, redox sensitive chaperone, sensor for oxidative stress, protects against oxidative stress

Question 8

PARK7 implicated in what? lower levels of DJ1 =?

Answer 8

many NDDs like PD, AD, ALS. lower DJ1 levels = DA neurons more susceptible to inflammatory mediated apoptosis.

Question 9

neurotrophic factors: which ones change in PD?

Answer 9

BDNF and GDNF reduced: stimulate growth + survival of DA neurons.

Question 10

3 animal models of PD

Answer 10

transgenic and knock out mice. injection of DA neuron specific toxins. injection of LPS.

Question 11

what DA specific tonx?

Answer 11

MPTP and 6 OH dopamine: mediates direct killing of DA neurons

Question 12

LPS injection?

Answer 12

PD mediated by inflammation, takes longer if injected systemically but faster when intracranial.

Question 13

MPTP: what? binds to? effects?

Answer 13

synthetic opioid drug. binds strongly to DA transporter, taken up by DA neurons –> metabolized into toxic cation MPP+ and interferes with ETC in mitochondria.

Question 14

common denominator of many NDDs?

Answer 14

inflammation

Question 15

inflammation in PD: activate what? where in brain? results in? elevated levels of?

Answer 15

microglia: results in loss of DA neurons. more microglia in SN + striatum. elevated levels of pro-inflam. mediators like TNFa, ILs, ROS

Question 16

nitrite: indicator for? levels?

Answer 16

indicator for NO free radicals: increased in CSF

Question 17

inflammation: treatment for PD?

Answer 17

anti-inflammatory drugs/treatments can slow progress + lessen severity of PD

Question 18

inflammation model of PD: initiate? inject what?

Answer 18

DA-neurodegeneration can be initiated by inflammogens, like LPS injection.

Question 19

inhibitors of inflmmation protect against?

Answer 19

LPS, MPTP, 6OH DA induced DA neurodegeneration.

Question 20

main in vitro model for studying PD pathogenesis?

Answer 20

primary rodent midbrain: then add LPS or MPTP, look at neurodegenration and inflammation

Question 21

current treatment examples

Answer 21

DA agonists like L-DOPA. COMT inhibitors, MAO inhibitors. anticholinergics. DBS. anti inflammatory drugs. stem cell replacement.

Question 22

problems with current treatment approaches

Answer 22

targeting, side effects, BBB, locus of action. relieve symptoms but don’t slow PD progression, eventually lose effectiveness