Parkinsons Disease Flashcards
(161 cards)
1
Q
approx. how many PD patients in the UK?
A
120,000
2
Q
What can PD be subdivided into?
A
young onset (5%), late onset, sporadic (95%) and familial
3
Q
What are the typical PD symptoms?
A
muscle rigidity and stiffness
resting rhythmic tremor
bradykinesia
postural instability/abnormalities
4
Q
What are the secondary PD symptoms?
A
depression, impotence, dizziness, drooling, dementia
5
Q
What is the basal ganglia?
A
a collection of sub-cortical nuclei situated within each cerebral hemisphere and upper brain stem
6
Q
What are the constituents of the BG?
A
caudate putamen globus pallidus (internal and external) STN substantia nigra (pars compacta and reticulata)
7
Q
What parts of the BG make up the striatum?
A
caudate and putamen
8
Q
Where does the BG recieve inputs from ?
A
all cortical areas
9
Q
Where does the BG project to?
A
the thalamus -> motor cortex
10
Q
What is the major input to the striatum?
A
the cerebral cortex
11
Q
Where is cortical information processed?
A
in the striatum -> BG out put nuclei (GP, SNpr)
12
Q
What are the neuropathological hallmarks of PD?
A
loss of nigrostriatal DA neurons
formation of Lewy Bodies
13
Q
What is lost in the nigrostriatum?
A
neuromelanin pigmented DA neurons in the pars compacta
14
Q
Where are Lewy Bodies particularly found?
A
as intraneuronal cytoplasmic inclusions within the pars compacta
15
Q
What are major constituents of Lewy Bodies?
A
a-synuclein
ubiquitin
16
Q
How many nerve cells does the SNpc normally have?
A
400,000
17
Q
When do PD symptoms onset from the SNpc?
A
when 80% of DA is lost in the putamen and 60% of SNpc neurons are lost
18
Q
What does loss of the projection to the putamen cause?
A
loss of DA inhibition to the striatum - shaking and tremor at rest
19
Q
What are the other neuronal losses in PD?
A
- noradrenergic neurons in the locus coreulus
- serotonergic neurons in the raphe nucleus
- cholinergic neurons in the dorsal motor nucleus of vagus
20
Q
What is the shape of a LB?
A
dense proteinacious core with a surrounding halo
21
Q
What are LB composed of?
A
filaments of ubiquitin and neurofilament proteins
22
Q
What are the sizes of filaments in the LB?
A
around 5-20nm
23
Q
What is a key component of LB?
A
a-synuclein
24
Q
What are the features of a-synuclein?
A
140aa protein
hydrophillic
natively unfolded
25
What is the structure of a-synuclein?
amphipathic region
a hydrophobic central region (non-amyloidogenic b-component)
acidic C-terminal region
26
Where are most mutations in a-synuclein found?
the amphipathic region
27
What gene is involved in a-synuclein mutations?
SNCA
28
Where is the SNCA gene mapped in PD?
4q21-q23
29
Which mutation was found to be a missense mutation?
A53T
30
What is found in a-synuclein in sporadic PD?
genetic variability in the promotor region of the gene - alters susceptibility to disease?
31
Where is a-synuclein normally expressed?
brain (mammalian) - particularly pre-synaptic nerve terminals
32
What do KO transgenic a-synuclein mice studies suggest about its function?
- role in synaptic vesicle recycling as can bind acidic phospholipid vesicles
- role in DA neurotransmission
33
What is found in mutant a-synuclein?
self-aggregates more readily than WT
34
How has mutant a-synuclein been shown to aggregate?
transgenic mice - have LB formation and neurodegeneration
| mice over-expressing A53T develop LB, mitochondrial damage and apoptosis of neocortical brainstem and MNs
35
What occurs with a-synculein in vitro?
overexpression of mutant or WT leads to ROS production and enhanced cell death
36
How does a-synuclein form LB?
unfolded or mutant a-synuclein form b-sheet rich oligomers which give rise to more stable amyloid-like fibrils
fibrils aggregate and form LB
37
What are the features of Parkin ?
E3 ligase - tags proteins for degradation via lysine residues
465 aa protein
relatively common mutation in PD
38
What is the main feature of Parkin mutations?
usually loss of function and tend to impair E3 ligase acitvity
39
What does UCH-L1 stand for?
ubiquitin C-terminal hydrolase L1
40
What does UCH-L1 do?
hydrolysis of c-terminal ubiquityl esters -> recycling ubiquitin
41
What is the dominant mutation found in UCH-L1 in one family?
I93M
42
What is a protective polymorphism in UCH-L1?
S18Y
43
Where is DJ-1 localised and what does this suggest?
highly localised to mitochondria
| suggests important modulator of mitochondrial function and a cellular monitor of oxidative stress
44
What have been found in DJ-1 mutations?
autosomal recessive with deletion or mis-sense mutations
45
What are the steps in the UPS?
1. Ubiquitin monomers activated by E1 and transferred to Ub-conjugating E2 enzyme
2. Added to proteins by E3
3. form poly-ub chains by attaching at lysine residues
4. poly-ub chains mark protein for degradation - small fragments
5. Poly-ub chains recycled by UCH-L1 and other enzymes
46
What is the gene for LRRK2?
park 8
47
What is the common mutation in LRRK2?
G2019S - gain of function
48
What does LRRK2 do normally?
phosphorylates substrates i.e. MKK3/6 for activation of JNK and p38 MAPK
49
What is the additional substrate for mLRRK2?
moesin
50
What does moesin normally do?
regulates neurite outgrowth and cytoskeleton
51
What does mLRRK2 interact with in the hippocampus?
a/b-tubulin - parts of the cytoskeleton
52
what is the suggested role of LRRK2 mutations in PD?
interfering with cytoskeletal motility and vesicular trafficking events
53
What are the two main hypothesis in PD?
misfolding and aggregation of proteins -> death of SNpc DA neurons
mitochondrial dysfunction and consequent ROS lead to cell death
54
What is the evidence for misfolding and aggregation of proteins?
abnormal deposits of protein in the brain is a feature of multiple neurodegenerative disorders
55
What evidence is there for abnormal protein conformation in inherited PD?
- pathogenic mutations directly inducing abnormal protein folding - a-synuclein
- pathogenic mutations that interfere with processing of misfolded proteins - Parkin, UCH-L1
56
What evidence is there for abnormal protein conformation in sporadic PD?
- direct protein damaging modifications ad indirect changes in processing of misfolded proteins have also been detected
- oxidative stress thought to be a possible trigger
57
What is the evidence for mitochondrial dysfunction and oxidative stress in PD?
- defects in oxidative phosphorylation suggested with MPTP block of complex I
- complex I abnormalities identified in PD
58
What is the process which is inhibited in complex I abnormalities?
- NADH binds to complex I and passes two electrons to FMN group
- FMN is reduced to FMNH2
- Electrons are passed to iron-sulphur proteins
- Fe3+ -> Fe2+
59
What does inhibition of complex I cause?
increase in ROS production
60
What can be formed in complex I inhibition?
Hydroxy radicals or reaction with NO to form OONO-
61
How do hydroxy radicals cause damage?
damage by reacting with nucleic acids, proteins and lipids
62
What markers suggest increased ROS in PD?
decreased glutathione antioxidant
| increased markers of oxidative damage
63
Why is it a suggestion of increased ROS -> neurodegeneration?
correlative - no data just yet
64
What happens to cause cell death in PD?
Programmed Cell Death
65
When in PCD crucial?
in normal development and as a homeostatic mechanism
66
What is the evidence for PCD in PD?
- increase in Bax-positive SNpc DA neurons
- increased neuronal expression of Bax
- presence of caspase-8, caspase-9 and Bcl-xL
67
What are the Toxin based animal models of PD?
6-OH-Da
Paraquat
Rotenone
MPTP
68
What are the gene based animal models of PD?
synuclein
| parkin
69
Why is 6-OH-DA induced toxicity efective?
selective for DA neurons - preferential uptake by DA transporter
70
Where does 6OHDA accumulate in neurons and what is its effect?
in the cytosol -> ROS and inactivates various molecule by generating quinones
71
What can be varied in 6OHDA model?
there are potentially different models depending on the location of injection into the brain
72
What happens with 6OHDA injection into the medial forebrain bundle?
extensive DA depletion
73
What happens with 6OHDA injection into the SNpc?
specific and more moderate DA depletion
74
What occurs with 6OHDA injection into the caudate putamen?
specific DA depletion
75
What form of rat are most appropriate for studying PD with 6OHDA model?
rats with partial lesions of the ventrolateral caudate for early and late PD
76
What is the advantage of studying the 6oHDA model?
good for assessing anti-PD actions of new drugs as unilateral striatal lesions causes quantifaibly asymetric circling behaviour
77
What are the disadvantages of the 6OHDA?
- not clear if mechanisms of cell death is similar to PD
- no LB and pathology differs to PD
- pathology varies with injection site
78
What does MPTP cause in humans and monkeys?
irreversible and severe PD syndrome characterised by tremor, rigidity, bradykinesia
79
What similarities does MPTP have to PD?
low dose -> preferential degeneration of putamen vs caudate DA nerve terminals
regional pattern of damage is similar to PD?
80
What are the difference of MPTP model to PD?
doesn't affect other monoaminergic neurosn (i.e. locus coreleus)
no LBs
81
What uses do MPTP models have?
- monkey model - assess novel treatments of PD
electrophys. showed hyperactivity of STN (key in PD) - lead to targeted DBS to reduce motor hyperactivity in patients
- mouse model enhance understanding of possible neurodegeneration mechanisms
82
What is the MPTP metabolism pathway?
- crosses BBB where converted to MPDP+ and then into MPP+ by unknown mechanism
- MPP+ released in to EC space and concentrated into DA neurons by DA transporter, DAT
83
What does MPP+ do in neurons?
- blocks complex I
- reduces ATP
- increases ROS
- interacts with cytosolic enzymes TOXIC
- sequesters into synaptic vesicles via VMAT - protective
84
What is paraquat?
a herbicide that induces toxin model of PD similar in structure to MPP+ although does not easily cross BBB
85
What is toxicity due to in paraquat model?
increased superoxide radicals - SNpc DA degeneration and a-synuclein inclusions
86
What is the advantage of the paraquat model?
may be useful to study role of a-synuclein in neurodegeneration
87
What is the disadvantage of the paraquat model?
not known if it is just DA neurons affected
88
What is Rotenone?
cytotoxic compounds which are widely used as insecticides and fish poison
89
What are the features of Rotenone?
highly lipophillic with access to most organs
| binds to same site as MPP+ and inhibits complex I
90
What is found in rotenone rats with IV?
selective DA degeneration and a-synuclein pos. inclusions
| abnormal postures and slow movement
91
What are the advantages of the rotenone model?
studying the relationship between aggregation formation and cell death
92
What is the disadvantage of the rotenone model?
widespread neurotoxic actions which are not DA selective
93
Why is it good to use genetic models of PD?
there is an expectation that the genetic and sporadic forms share similar pathogenic mechanisms - genetic models can focus on pathways
94
What does the a-synuclein model severity depend on?
the region of promotor used to make the transgene
95
What is found with overexpression of a-synuclein in mice?
causes neurochemical deficits in the nigrostriatal pathway, behavioural anomalies and a-synuclein accumulation
also accelerated age related loss of DA neurons
96
What can be concluded from the a-synuclein mice?
that other factors probably contribute to the full human PD phenotype
97
What have parkin models focussed on?
parkin KO as the PD mutations are loss of function
98
What happens in quaking mouse mutant?
spontaneous deletion of parkin. myelin deficiency and enhanced DA metabolism. behavioural deficits and tremor in trunk and extremities
99
What is the defect in the Parkin KO mouse?
defective exon 3
100
What happens in parkin KO mouse?
progressive motor anomalies and deficits in sensori-motor integration
paradoxically have increased basal release of striatal DA and reduced striatal neuronal excitability
reduced levels of proteins in mitochondrial function
oxidative stress
101
What is the disadvantage of the genetic models?
neither model has full spectrum of anomalies found in humans
102
Where are highest levels of DA found?
corpus striatum (largest), limbic system and hypothalamus
103
How is DA synthesised?
from tyrosine to dopa
| decarboxylation to DA
104
What metabolises DA?
MAO-B and COMT
105
What are the products of DA metabolism?
Dopac
| Homovanillate - HVA
106
What are the two major classes of DA receptor?
D1
| D2
107
What are the subtypes and function of D1 class?
D1 and D5 - stimulate AC to produce cAMP
108
What are the subtypes and function of D2 class?
D2,3,4 - inhibit AD activity
109
Where are D1 class normally found?
brain and smooth muscle - mostly post-synaptic inhibition
110
Where are D2 class normally found?
brain, CV system, presynaptic nerve terminals - pre/post synaptic inhibition
111
How is DA release modulated?
D3 autoreceptors
112
How is DA synthesis and metabolism modulated?
D2 autoreceptors
113
What are the 3 main DA pathways in the brain?
```
Nigrostriatal system (motor) - SN -> corpus striatum
Mesolimbocortical system - emotion and rewards
tuberohypophyseal system (endocrine control) - hypothalamus
```
114
Which receptors are found on dynorphin neurons?
D1
115
Where are dynorphin neurons?
in the striatum
116
How does the SNc affect the dynorphin neurons?
stimulates the striatum -> direct pathway (voluntary movement)
117
Which receptors are found on the enkephalin neurons?
D2
118
Where are the enkephalin neurons found?
striatum
119
What is the effect of the SNc on the enkephalin neurons?
inhibits the striatum -> indirect pathway (involuntary movement)
120
What happens to the pathway in PD?
reduced inhibition of indirect pathway (tremor)
| increased inhibition of direct pathway (bradykinesia)
121
What are the current pharmacological therapy options in PD?
- drugs that increase endogenous production
- drugs that mimic DA action
- drugs that prevent DA degradation endogenously (MAO-B Inhibitors) or exogenously (COMT-Is)
- drugs that release DA
- muscarinic cholinergic antagonists
122
How does levodopa cross the brain?
as a precursor
123
what is levodopa usually combined with and why?
a dopa decarboxylase inhibitor to reduce the dose needed and decrease side-effects
124
what does the dopa decarboxylase inhibitor do in the periphery?
prevents levodopa conversion to DA but doesn't cross the BBB so decarboxylation can occur rapidly
125
What are the therapeutic features of levodopa?
well absorbed by small intestine via active transport
| short plasma half life
126
How do patients normally improve at the start of treatment?
80% improved motor function
| 20% motor function restored
127
Why does levodopa effectiveness reduce?
natural progression of the disease
receptor downregulation
other compensatory mechanisms
128
What are the slow-developing side-effects of levodopa?
- dyskinesia (involuntary writing movements) in face and limbs (around 2 years of starting)
- on-off effect - rapid fluctuations in clinical state - worsening then recovery ?due to plasma fluctuations
129
What are the acute side-effects of levodopa?
- nausea and anorexia
- hypotension
- pyschological i.e. hallucinations and delusions
130
What is Selegine?
MAO-B inhibitor
131
What does selegine do?
selective for MAO-B which predominates DA-containing neurons
132
What is the advantage of selegine?
lacks unwanted peripheral side effects unlike unselective MAO-Is - can't eat cheese because increase in tyrosine
133
When choosing DA receptors agonists, why is it preferable to choose D2 selective than D1?
produces consistent anti-parkinsonism unlike D1 which may have broader effects
134
Give an example of a D2 R agonist?
bromocryptine
| long duration of action (t1/2 = 6-8 hours)
135
Why may doses of DA-R agonists be limited?
similar side effects to levodopa
136
How can ACh influence the brain stem?
SN-> DA-> ACh -> Brain stem
137
Why is the ACh imbalance a problem?
lack of DA causes increase in ACh
138
Give an example of an mAChR antagonist?
Benztropine
139
What effects do mAChRs have?
- excitatory on striatal neurons (opposite to DA)
| - Presynaptic inhibition of DA terminals
140
Why are mAChR antagonists limited in their use?
some bad side-effects : impaired vision and urinary retention, also dry mouth and constipation
141
When are mAChR antagonists mainly used?
in parkinsonism caused by anti-psychotics
142
Where are Adenosine A2A receptors found?
in the CNS, enriched in the striatum, high levels in D2R expressing GABAergic striatal pallidal neurons
143
What does activation of the A2A Rs do?
opposes the effects of D2Rs - hence antagonists would be useful
144
What are the issues with using A2AR antagonists?
have systemic and CNS side effects
145
What are the systemic side effects of A2A R antagonists?
inflammation
| ischemic tissue damage in heart, renal, liver
146
What are the CNS side-effect of A2A R antagonists?
psychosis and insomnia
147
What does the endocannabinoid system modulate?
GABAergic and glutamergic transmission in the BG
148
What can be seen in PD patients re: CB?
decrease in CB1 Rs
149
Where are CB2Rs expressed in brain?
expressed in BG - impairement linked to dyskinesia
150
What was found in CSF of PD patients?
doubles AEA levels
151
What do CB1agonists do?
reduce excitotoxicity - improve motor symptoms although results variable
152
What does neural transplantation involve?
injection of dissociated fetal cells into the SNc
153
What has been found in neural transplantation in humans?
- success rate variable and benefits are usually short-lived
- post-mortem studies show that transplants can survive and establish synaptic connections
- can remain healthy and maintain function for 15-18 years
154
For whom, is DBS an alternative for?
patients with intractable tremor and/or affected by complications of levodopa
155
What is targeted in DBS treatment?
STN and GPi
156
Which area is superior to target in DBS?
STN as it produces a more pronounced anti-kinetic effect
157
Why is gene-therapy appropriate in PD?
has specific neuro-anatomical pathology
158
Why is GAD an ideal target in gene therapy for PD?
the STN is disinhibited causing the tremor and bradykinesia however inhibiting it with GABA is a good idea
GAD helps synthesise GABA
159
What has been found in the studies of GAD gene therapy so far?
no adverse affects in small studies
| monkeys have small improvements in motor activity
160
Why may GDNF be an ideal gene therapy for PD?
promotes DA neurons survival and regeneration in rodents and primates
variable success in humans
161
What are the issues with gene therapy?
- short term results meaning patients have to undergo therapy every few months
- immune response may destroy viral vector
- toxicity if viral vector mutates and becomes pathogenic
