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BMSC - Neuroanatomy > PD Mechanisms > Flashcards

PD Mechanisms Flashcards

1
Q

What are the main group of genes implicated in PD?

A

Park 1-11

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2
Q

What is Parkin?

A

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

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3
Q

What is the role of Parkin?

A

It is needed to tag proteins for degradation with Ubiquitin

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4
Q

Outline the abnormal action of Parkin in PD

A

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

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5
Q

What is the normal function of UCHL1

A

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

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6
Q

What is the most common UCHL1 mutation in inherited PD?

A

I93M

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7
Q

What is the known protective polymorphism for PD in UCHL1

A

S18Y

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8
Q

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

A

I93M and S18Y are both mutated on UCHL1

Both alter the function of UCHL1

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9
Q

What is the normal Ub-proteasomal pathway

A 
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)
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10
Q

What is DJ-1?

A

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

(aka PARK7)

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11
Q

Which type of PD is DJ-1 implicated in?

A

AR

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12
Q

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

A

Deletion to abolish function

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

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13
Q

On which chromosome is alpha-synuclein?

A

Chromosome 4q21-q23

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14
Q

Which mutations have been found in alpha-synuclein?

A

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

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15
Q

What is the normal function of alpha-synuclein?

A

Regulates synaptic vesicle size with relevance to storage of DA

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16
Q

What does mutant alpha-synuclein do?

A

Self-aggregates and forms Lewy Bodies

17
Q

What is seen in transgenic mice with A53T mutations?

A

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

18
Q

What is LRRK the same as?

A

PARK8

19
Q

What does PARK8 code for?

A

Dardarin

20
Q

Which known mutation increases kinase activity?

A

G2019S

21
Q

What is the normal role of LRRK?

A

Phosphorylate substances needed for MAPK and JNK pathways

22
Q

What is the action of mutant LRRK?

A

Interacts with the cytoskeleton of cells to affect neurite outgrowth

23
Q

What is a lewy body?

A

Intracellular inclusion

Dense core, peripheral halo

24
Q

What do Lewy bodies contain?

A

Ubiquitin protein
Neurofilament protein
Alpha-synuclein (fibrillar form)

25
Q

What occurs in transgenic mice with alpha-synuclein mutations?

A

Lewy body formation

Neurodegeneration

26
Q

What is moesin?

A

A substrate for mutant LRRK2

Protein which regulates neurite outgrowth and cytoskeleton function

27
Q

Which component of the cytoskeleton does LRRK2 bind to?

A

alpha/beta tubulin

28
Q

What are the two main theories of PD?

A

Misfolding and aggregation of proteins cause SNpc DA neuron death

Mitochondrial dysfunction and oxidative damage lead to cell death

29
Q

What does MPTP do in PD?

A

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

30
Q

How does complex I inhibition increase superoxide formation?

A

Forms toxic hydroxyl radicals

React with NO to form peroxynitrite

31
Q

Which findings are consistent with increased ROS in PD?

A

Oxidative damage biomarkers are increased in PD

Anti-oxidant glutathione reduced in PD

32
Q

What is the evidence for programmed cell death in parkinsons?

A

Increase in number of Bax-positive SNpc DA neurons

this is a PCD molecule

33
Q

How does DJ-1 work?

A

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

34
Q

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

A

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

Johri A, Beal MF, 2012

BMSC - Neuroanatomy (17 decks)

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