PD Mechanisms Flashcards
What are the main group of genes implicated in PD?
Park 1-11
What is Parkin?
An E3 ligase, 465 amino acid protein with a modular structure
What is the role of Parkin?
It is needed to tag proteins for degradation with Ubiquitin
Outline the abnormal action of Parkin in PD
Loss of function
Improper targeting of substrates for proteasomal degradation
So toxic substances accumulate
What is the normal function of UCHL1
Catalyse the hydrolysis of C terminal ubiquityl esters to recycle ubiquitin to misfolded proteins
What is the most common UCHL1 mutation in inherited PD?
I93M
What is the known protective polymorphism for PD in UCHL1
S18Y
How do we know that Ub-protease activity is important in PD?
I93M and S18Y are both mutated on UCHL1
Both alter the function of UCHL1
What is the normal Ub-proteasomal pathway
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)
What is DJ-1?
A cellular monitor of oxidative stress, highly expressed in the cytosol, and involved in normal mitochondrial functioning
(aka PARK7)
Which type of PD is DJ-1 implicated in?
AR
Which kind of mutations have been observed in DJ-1 in PD?
Deletion to abolish function
Missense which inserts a proline into the alpha-helical region to it cant function
On which chromosome is alpha-synuclein?
Chromosome 4q21-q23
Which mutations have been found in alpha-synuclein?
A53T (Italian)
A30P (German)
E46K (Spanish)
What is the normal function of alpha-synuclein?
Regulates synaptic vesicle size with relevance to storage of DA
What does mutant alpha-synuclein do?
Self-aggregates and forms Lewy Bodies
What is seen in transgenic mice with A53T mutations?
Develop intraneuronal inclusiosn
DNA damage in the mitochondria
Apoptosis of the neocortical, brainstem and MN cells
Increased ROS
What is LRRK the same as?
PARK8
What does PARK8 code for?
Dardarin
Which known mutation increases kinase activity?
G2019S
What is the normal role of LRRK?
Phosphorylate substances needed for MAPK and JNK pathways
What is the action of mutant LRRK?
Interacts with the cytoskeleton of cells to affect neurite outgrowth
What is a lewy body?
Intracellular inclusion
Dense core, peripheral halo
What do Lewy bodies contain?
Ubiquitin protein
Neurofilament protein
Alpha-synuclein (fibrillar form)
What occurs in transgenic mice with alpha-synuclein mutations?
Lewy body formation
Neurodegeneration
What is moesin?
A substrate for mutant LRRK2
Protein which regulates neurite outgrowth and cytoskeleton function
Which component of the cytoskeleton does LRRK2 bind to?
alpha/beta tubulin
What are the two main theories of PD?
Misfolding and aggregation of proteins cause SNpc DA neuron death
Mitochondrial dysfunction and oxidative damage lead to cell death
What does MPTP do in PD?
Inhibits complex I to block electron transport chain function
This increases ROS superoxide formation
How does complex I inhibition increase superoxide formation?
Forms toxic hydroxyl radicals
React with NO to form peroxynitrite
Which findings are consistent with increased ROS in PD?
Oxidative damage biomarkers are increased in PD
Anti-oxidant glutathione reduced in PD
What is the evidence for programmed cell death in parkinsons?
Increase in number of Bax-positive SNpc DA neurons
this is a PCD molecule
How does DJ-1 work?
Migrates to mitochondria rapidly via chemical chaperones upon sensing of oxidative stress
What evidence is there that DJ-1 malfunction is involved in PD?
Loss of function of DJ-1 a/w decrease in complex I activity, leading to ROS and damage
Johri A, Beal MF, 2012
