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Parkinson's Disease Flashcards

1
Q

Name the 3 main categories of PD symptoms

A

Premotor
Motor
Postmotor

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2
Q

Name the premotor symptoms of PD

A

Depression
Loss of olfaction
REM sleep disorder

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3
Q

Name the motor symptoms of PD

A

Bradykinesia
Rigidity
Resting tremor
Masked face

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4
Q

Name the postmotor symptoms of PD

A

Dementia

Visual hallucinations

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5
Q

What are the two main pathologies seen in PD?

A

Progressive loss of DAergic neurons in SNpc

Lewy bodies in remaining SN neurons

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6
Q

What are the 2 main treatment types for PD currently?

A

Deep brain stimulation

Drugs

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7
Q

Which drugs are currently used to treat PD?

A

L-Dopa
MAOB/COMT inhibitors
DA agonists

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8
Q

Through which brain areas do LBs spread?

A

Brainstem -> midbrain via SN -> cerebral cortex

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9
Q

Where in the periphery can LBs be found in PD?

A

Enteric neurons
Vagus nerve
Autonomic ganglia

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10
Q

What is the main component of LBs?

A

Alpha-synuclein

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11
Q

What is incidental LB disease?

A

LBs mainly in brainstem
Mild DAergic neuronal loss
Clinically normal
Diagnosed postmortem - could be presymptomatic PD

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12
Q

What are the 3 main types of PD risk factors?

A

Increased age
Environment
Genetics

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13
Q

Name 5 genes that increase familial PD risk

A 
SNCA
Parkin
PINK1
LRRK2
GBA
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14
Q

Name 2 environmental factors that increase PD disease risk

A

Living near metal alloy industries

Well water drinking

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15
Q

Name 2 environmental factors that decrease PD disease risk

A

Smoking

Coffee drinking

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16
Q

What is the effect of MPTP?

A

Destroys SN DAergic neurons

Causes permanent Parkinsonian symptoms

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17
Q

What is the physiological function of alpha-synuclein?

A

Unknown

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18
Q

What is the effect of alpha-synuclein KO in mice?

A

Fairly normal
Altered DA release
Some neuronal dysfunction

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19
Q

Name an autosomal dominant cause of PD

A

SNCA

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20
Q

What is the effect of an SNCA locus duplication?

A

3 copies of gene - increased alpha-syn

PD development in 40s

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21
Q

What is the effect of an SNCA locus triplication?

A

4 copies of gene - greatly increased alpha-syn

PD development in 30s

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22
Q

What are the steps of alpha-synuclein aggregation?

A 
Soluble monomer (normal/B-sheet-rich)
Soluble oligomer (normal/B-sheet-rich)
Protofibril
Fibril
LB (inclusion/aggregate)
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23
Q

Which alpha-synuclein species are thought to be toxic?

A

Soluble oligomers

Protofibrils

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24
Q

What is the effect of transplanting foetal tissue into PD patients and what could explain this?

A

LBs form in graft

Could be LB transmission - could be host environment causes dysfunction in graft causing alpha-syn aggregation

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25
What are the structures of the normal and mutant alpha-synuclein monomers?
Normal - alpha-helices | Mutant - beta-sheets
26
What is permissive templating?
Exposing normal alpha-syn to misfolded B-sheet alpha-syn decreases energy required for normal protein unfolding Increases chance of refolding Increases chance of aggregate formation
27
Name 3 ways in which alpha-syn can be transferred between cells
Exosomes Free in solution Tunneling nanotubes
28
What is the effect of DA on alpha-synuclein?
Causes protofibril formation
29
How does MPTP cause parkinsonism?
Uncharged - crosses BBB Metabolised to MPP+ - substrate for DAT - uptake into DAergic neurons Opposite charge to -ve mito matrix - crosses mito membrane Inhibits complex I function Decreases ATP production, increases ROS (oxi stress) DAergic neuron death
30
How does alpha-synuclein interact with lysosome functioning?
Alpha-syn degraded by chaperone-mediated autophagy | Alpha-syn aggregates removed by macroautophagy
31
How is mitochondrial function altered in idiopathic PD patients?
Decreased complex I activity | In SN tissue, platelet mitochondria
32
Which mitochondrial ageing phenomenon is further increased in PD SN neurons?
Higher mtDNA levels with deletion
33
How is the sensitivity of DAergic SN neurons to mitochondrial respiratory chain toxins altered in PD and why might this be?
Increased Could be due to oxidative stress Could be due to defective degradation of damaged mitos - due to autophagy/lysosome defects
34
What is the overall role of parkin and PINK1?
Prevent fusion back of damaged mitos fragmented by fission
35
Why might DAergic neurons be so vulnerable to mitochondrial dysfunction in PD?
High spontaneous burst/pacemaking activity - high energy demands High Ca2+ fluxes - more vulnerable to Ca2+ dysregulation
36
How might alpha-synuclein affect mito function?
Inhibit mitochondrial respiratory chain - possibly complex I
37
What are the 4 main methods of alpha-synuclein degradation?
Ubiquitin proteasome system Macroautophagy Chaperone-mediated autophagy Mitophagy
38
What does the ubiquitin proteasome system involve?
Unfolded protein tagged with ubiquitin | Sent to proteasome for degradation
39
What does macroautophagy involve?
Autophagosomes (double-membrane vesicles) form around proteins Fuse with lysosomes
40
What does chaperone-mediated autophagy involve?
Unfolded protein associates with chaperone complex | Sent to lysosome for degradation
41
What does mitophagy involve?
Only degradation method for misfolded alpha-syn Whole mitochondrial engulfed by autophagosomes Fuse with lysosomes
42
How is UPS functioning altered in PD?
Decreased proteasomal activity in SN
43
Are proteins in LBs ubiquitinated in PD?
Yes
44
How is macroautophagy functioning altered in PD?
Fewer lysosomes in SN | More autophagosomes in SN
45
How is CMA functioning altered in PD?
Decreased CMA protein levels
46
How does VPS35 affect PD risk?
Autosomal dominant cause
47
What is the physiological function of VPS35?
Component of retromer complex | Retromer enables retrograde transfer of MPR from endosome back to trans-Golgi network
48
What is the role of the mannose-6-phosphate receptor (MPR)?
Transfers lysosomal enzymes from Golgi to endosomes - then lysosomes
49
What is the proposed pathological mechanism of VPS35 in PD?
Retromer defect - MPR not returned to Golgi Incomplete transfer of lysosomal enzymes to lysosomes Impaired protein degradation - alpha-syn accumulation
50
What is the physiological role of GBA1?
Encodes glucocerebrosidase - lysosomal enzyme | Catalyses glucocerebroside breakdown
51
What do recessive mutations in GBA1 cause and what does this disease involve?
Gauchers disease | Lysosomal storage dysfunction
52
What is the effect of a heterozygous recessive GBA1 mutation?
Increased PD risk
53
What is the proposed pathological mechanism of GBA1 in Gauchers disease?
Loss-of-function Accumulation of glucocerebroside in lysosomes Lysosome dysfunction - impairs mitophagy - impairs MRC activity Induces unfolded protein response
54
What are the 2 possible mechanisms by which GBA1 mutation may lead to neuronal death in PD?
GBA1 misfolding in ER causes UPR - decreases translation - causes apoptosis GBA1 misfolding in ER - targeted for degradation - decreases GBA1 in lysosome - increases glucocerebroside - causes lysosome dysfunction - decreases alpha-syn degradation
55
What is the physiological role of ATP13A2?
Transports Zn2+ into lysosome
56
What is the pathological role of ATP13A2?
Loss-of-function | Affects lysosomal function - impairs protein degradation
57
Which LRRK2 variant increases PD risk?
G2019S
58
What is the physiological role of LRRK2?
Unknown Kinase Linked to autophagy, microglial mobility, mito function
59
What is the pathological role of LRRK2 with a G2019S mutation?
Increased kinase activity | Effect unknown
60
What is the effect of a PINK1/parkin KO?
MRC defects
61
What is the physiological role of DJ-1?
Oxidative stress sensor | Translocated to mitos in response to oxi stress - antioxidant role - protective
62
What does mutant DJ-1 PD involve?
Abnormal symptoms - dystonia, psychiatric features
63
What is the pathological role of DJ-1?
Loss-of-function | No translocation to mitos in response to oxi stress - impairs defence against damage
64
What does oxidative damage modify?
Amino acids DNA (inc. mtDNA) Lipids
65
How has oxidative stress been linked to idiopathic PD?
Increased oxi stress
66
Mouse models deficient in the expression of which genes show increased oxi stress?
Parkin PINK1 DJ-1
67
What are the 3 sources of ATP in the cell and which is the main source?
ETC - main source Krebs cycle Glycolysis
68
What is the effect of mito damage on mito membrane potential?
Depolarisation
69
Why is mito function particularly important in neurons?
Neurons have very little glycolysis - dependent on mitos for ATP Many energy-demanding processes in neurons
70
How are ROS formed in the mitochondria?
Electron leak from ETC | Electrons react with free oxygen
71
What are the roles of antioxidant enzymes?
Decrease ROS number | Decrease ROS toxicity - by converting to different ROS
72
What are the 4 effects of age on mitos?
Decreased antioxidant levels Decreased protein degradation Increased mtDNA damage - by ROS Electron leak decreases H+ gradient - decreases ATP production - decreases mito membrane potential - mPTP opening - cell death
73
What causes mPTP opening?
Increased mito Ca2+ | Mito depolarisation
74
What is the effect of mPTP opening?
H+ efflux - loss of H+ gradient Decreased ATP production Cell death
75
What happens to fissioned mitos?
Fusion or mitophagy
76
What is the physiological role of PINK1?
Regulates mito Ca2+ efflux - via IMM Ca2+/Na+ exchanger
77
What is the effect of PINK1 deficiency?
Impairs Na+/Ca2+ exchanger in IMM Increased mito Ca2+ - decreases buffering capacity Increased cytosolic Ca2+ - decreases mPTP opening threshold Increased NADPH oxidase activity - increased ROS Opens mPTP Cell death
78
How do excess fission and fusion affect synapses?
Decreased ATP at synapse
79
Which mitochondrial process are PINK1 and parkin involved in?
Mitophagy
80
Name 7 mechanisms of mitochondrial quality control
``` Mito chaperones Mito proteases Cytoplasmic UPS mtUPR Mitochondria derived vesicles (MDRs) Mitophagy Apoptosis ```
81
What is the role of mitochondrial chaperones?
Fold protein once inside mito
82
What is the role of mitochondrial proteases?
Break down improperly-folded proteins
83
What is the role of cytoplasmic UPS?
Ubiquitinates faulty proteins
84
What is the role of mtUPR?
Damaged mito protein causes signal to nucleus - increases transcription of chaperones and proteases
85
What are mitochondria derived vesicles (MDRs)?
Damaged proteins cluster - form vesicles budding off mitos | Fuse with lysosome - degraded
86
What type of parkin mutation increases PD risk?
Autosomal recessive | Loss-of-function
87
What is the role of parkin in mitophagy?
Recruited to damaged mitos | E3 ubiquitin ligase - tags proteins for degradation with ubiquitin
88
What type of PINK1 mutation increases PD risk?
Autosomal recessive | Loss-of-function
89
How do PINK1 and parkin cause mitophagy?
Mitochondrial depolarisation PINK1 accumulates on OMM Recruits parkin to mitos PINK1 phosphorylates parkin and ubiquitin chains on mito membrane proteins (e.g. Mfn1/2) Activates parkin - builds more ubiquitin chains on mito membrane proteins - amplifies signal Marks mito for degradation by mitophagy
90
A mutation in which gene causes juvenile Parkinsonism with additional pyramidal signs?
Fbxo7
91
What is the role of Fbxo7?
Facilitates parkin-mediated Mfn1 ubiquitination | May recruit parkin to mitos
92
What is required for Fbxo7 translocation to mitos?
PINK1

NEUR0010 (9 decks)

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