PD Mechanisms

Question 1

What are the main group of genes implicated in PD?

Answer 1

Park 1-11

Question 2

What is Parkin?

Answer 2

An E3 ligase, 465 amino acid protein with a modular structure

Question 3

What is the role of Parkin?

Answer 3

It is needed to tag proteins for degradation with Ubiquitin

Question 4

Outline the abnormal action of Parkin in PD

Answer 4

Loss of function
Improper targeting of substrates for proteasomal degradation
So toxic substances accumulate

Question 5

What is the normal function of UCHL1

Answer 5

Catalyse the hydrolysis of C terminal ubiquityl esters to recycle ubiquitin to misfolded proteins

Question 6

What is the most common UCHL1 mutation in inherited PD?

Answer 6

I93M

Question 7

What is the known protective polymorphism for PD in UCHL1

Answer 7

S18Y

Question 8

How do we know that Ub-protease activity is important in PD?

Answer 8

I93M and S18Y are both mutated on UCHL1

Both alter the function of UCHL1

Question 9

What is the normal Ub-proteasomal pathway

Answer 9

E1 activated
Ub transferred to E2
E3 transfers Ub to target
Ub attachment signals for degradation
UCHL-1 recycles Ub to free monomers (to be used again)

Question 10

What is DJ-1?

Answer 10

A cellular monitor of oxidative stress, highly expressed in the cytosol, and involved in normal mitochondrial functioning

(aka PARK7)

Question 11

Which type of PD is DJ-1 implicated in?

Answer 11

AR

Question 12

Which kind of mutations have been observed in DJ-1 in PD?

Answer 12

Deletion to abolish function

Missense which inserts a proline into the alpha-helical region to it cant function

Question 13

On which chromosome is alpha-synuclein?

Answer 13

Chromosome 4q21-q23

Question 14

Which mutations have been found in alpha-synuclein?

Answer 14

A53T (Italian)
A30P (German)
E46K (Spanish)

Question 15

What is the normal function of alpha-synuclein?

Answer 15

Regulates synaptic vesicle size with relevance to storage of DA

Question 16

What does mutant alpha-synuclein do?

Answer 16

Self-aggregates and forms Lewy Bodies

Question 17

What is seen in transgenic mice with A53T mutations?

Answer 17

Develop intraneuronal inclusiosn
DNA damage in the mitochondria
Apoptosis of the neocortical, brainstem and MN cells
Increased ROS

Question 18

What is LRRK the same as?

Answer 18

PARK8

Question 19

What does PARK8 code for?

Answer 19

Dardarin

Question 20

Which known mutation increases kinase activity?

Answer 20

G2019S

Question 21

What is the normal role of LRRK?

Answer 21

Phosphorylate substances needed for MAPK and JNK pathways

Question 22

What is the action of mutant LRRK?

Answer 22

Interacts with the cytoskeleton of cells to affect neurite outgrowth

Question 23

What is a lewy body?

Answer 23

Intracellular inclusion

Dense core, peripheral halo

Question 24

What do Lewy bodies contain?

Answer 24

Ubiquitin protein
Neurofilament protein
Alpha-synuclein (fibrillar form)

Question 25

What occurs in transgenic mice with alpha-synuclein mutations?

Answer 25

Lewy body formation | Neurodegeneration

Question 26

What is moesin?

Answer 26

A substrate for mutant LRRK2 | Protein which regulates neurite outgrowth and cytoskeleton function

Question 27

Which component of the cytoskeleton does LRRK2 bind to?

Answer 27

alpha/beta tubulin

Question 28

What are the two main theories of PD?

Answer 28

Misfolding and aggregation of proteins cause SNpc DA neuron death Mitochondrial dysfunction and oxidative damage lead to cell death

Question 29

What does MPTP do in PD?

Answer 29

Inhibits complex I to block electron transport chain function This increases ROS superoxide formation

Question 30

How does complex I inhibition increase superoxide formation?

Answer 30

Forms toxic hydroxyl radicals | React with NO to form peroxynitrite

Question 31

Which findings are consistent with increased ROS in PD?

Answer 31

Oxidative damage biomarkers are increased in PD | Anti-oxidant glutathione reduced in PD

Question 32

What is the evidence for programmed cell death in parkinsons?

Answer 32

Increase in number of Bax-positive SNpc DA neurons | this is a PCD molecule

Question 33

How does DJ-1 work?

Answer 33

Migrates to mitochondria rapidly via chemical chaperones upon sensing of oxidative stress

Question 34

What evidence is there that DJ-1 malfunction is involved in PD?

Answer 34

Loss of function of DJ-1 a/w decrease in complex I activity, leading to ROS and damage Johri A, Beal MF, 2012