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NEUR0010 > Parkinson's Disease > Flashcards

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
Q

What are the structures of the normal and mutant alpha-synuclein monomers?

A

Normal - alpha-helices

Mutant - beta-sheets

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26
Q

What is permissive templating?

A

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

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27
Q

Name 3 ways in which alpha-syn can be transferred between cells

A

Exosomes
Free in solution
Tunneling nanotubes

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28
Q

What is the effect of DA on alpha-synuclein?

A

Causes protofibril formation

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29
Q

How does MPTP cause parkinsonism?

A

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

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30
Q

How does alpha-synuclein interact with lysosome functioning?

A

Alpha-syn degraded by chaperone-mediated autophagy

Alpha-syn aggregates removed by macroautophagy

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31
Q

How is mitochondrial function altered in idiopathic PD patients?

A

Decreased complex I activity

In SN tissue, platelet mitochondria

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32
Q

Which mitochondrial ageing phenomenon is further increased in PD SN neurons?

A

Higher mtDNA levels with deletion

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33
Q

How is the sensitivity of DAergic SN neurons to mitochondrial respiratory chain toxins altered in PD and why might this be?

A

Increased
Could be due to oxidative stress
Could be due to defective degradation of damaged mitos - due to autophagy/lysosome defects

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34
Q

What is the overall role of parkin and PINK1?

A

Prevent fusion back of damaged mitos fragmented by fission

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35
Q

Why might DAergic neurons be so vulnerable to mitochondrial dysfunction in PD?

A

High spontaneous burst/pacemaking activity - high energy demands
High Ca2+ fluxes - more vulnerable to Ca2+ dysregulation

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36
Q

How might alpha-synuclein affect mito function?

A

Inhibit mitochondrial respiratory chain - possibly complex I

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37
Q

What are the 4 main methods of alpha-synuclein degradation?

A

Ubiquitin proteasome system
Macroautophagy
Chaperone-mediated autophagy
Mitophagy

38
Q

What does the ubiquitin proteasome system involve?

A

Unfolded protein tagged with ubiquitin

Sent to proteasome for degradation

39
Q

What does macroautophagy involve?

A

Autophagosomes (double-membrane vesicles) form around proteins
Fuse with lysosomes

40
Q

What does chaperone-mediated autophagy involve?

A

Unfolded protein associates with chaperone complex

Sent to lysosome for degradation

41
Q

What does mitophagy involve?

A

Only degradation method for misfolded alpha-syn
Whole mitochondrial engulfed by autophagosomes
Fuse with lysosomes

42
Q

How is UPS functioning altered in PD?

A

Decreased proteasomal activity in SN

43
Q

Are proteins in LBs ubiquitinated in PD?

A

Yes

44
Q

How is macroautophagy functioning altered in PD?

A

Fewer lysosomes in SN

More autophagosomes in SN

45
Q

How is CMA functioning altered in PD?

A

Decreased CMA protein levels

46
Q

How does VPS35 affect PD risk?

A

Autosomal dominant cause

47
Q

What is the physiological function of VPS35?

A

Component of retromer complex

Retromer enables retrograde transfer of MPR from endosome back to trans-Golgi network

48
Q

What is the role of the mannose-6-phosphate receptor (MPR)?

A

Transfers lysosomal enzymes from Golgi to endosomes - then lysosomes

49
Q

What is the proposed pathological mechanism of VPS35 in PD?

A

Retromer defect - MPR not returned to Golgi
Incomplete transfer of lysosomal enzymes to lysosomes
Impaired protein degradation - alpha-syn accumulation

50
Q

What is the physiological role of GBA1?

A

Encodes glucocerebrosidase - lysosomal enzyme

Catalyses glucocerebroside breakdown

51
Q

What do recessive mutations in GBA1 cause and what does this disease involve?

A

Gauchers disease

Lysosomal storage dysfunction

52
Q

What is the effect of a heterozygous recessive GBA1 mutation?

A

Increased PD risk

53
Q

What is the proposed pathological mechanism of GBA1 in Gauchers disease?

A

Loss-of-function
Accumulation of glucocerebroside in lysosomes
Lysosome dysfunction - impairs mitophagy - impairs MRC activity
Induces unfolded protein response

54
Q

What are the 2 possible mechanisms by which GBA1 mutation may lead to neuronal death in PD?

A

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
Q

What is the physiological role of ATP13A2?

A

Transports Zn2+ into lysosome

56
Q

What is the pathological role of ATP13A2?

A

Loss-of-function

Affects lysosomal function - impairs protein degradation

57
Q

Which LRRK2 variant increases PD risk?

A

G2019S

58
Q

What is the physiological role of LRRK2?

A

Unknown
Kinase
Linked to autophagy, microglial mobility, mito function

59
Q

What is the pathological role of LRRK2 with a G2019S mutation?

A

Increased kinase activity

Effect unknown

60
Q

What is the effect of a PINK1/parkin KO?

A

MRC defects

61
Q

What is the physiological role of DJ-1?

A

Oxidative stress sensor

Translocated to mitos in response to oxi stress - antioxidant role - protective

62
Q

What does mutant DJ-1 PD involve?

A

Abnormal symptoms - dystonia, psychiatric features

63
Q

What is the pathological role of DJ-1?

A

Loss-of-function

No translocation to mitos in response to oxi stress - impairs defence against damage

64
Q

What does oxidative damage modify?

A

Amino acids
DNA (inc. mtDNA)
Lipids

65
Q

How has oxidative stress been linked to idiopathic PD?

A

Increased oxi stress

66
Q

Mouse models deficient in the expression of which genes show increased oxi stress?

A

Parkin
PINK1
DJ-1

67
Q

What are the 3 sources of ATP in the cell and which is the main source?

A

ETC - main source
Krebs cycle
Glycolysis

68
Q

What is the effect of mito damage on mito membrane potential?

A

Depolarisation

69
Q

Why is mito function particularly important in neurons?

A

Neurons have very little glycolysis - dependent on mitos for ATP
Many energy-demanding processes in neurons

70
Q

How are ROS formed in the mitochondria?

A

Electron leak from ETC

Electrons react with free oxygen

71
Q

What are the roles of antioxidant enzymes?

A

Decrease ROS number

Decrease ROS toxicity - by converting to different ROS

72
Q

What are the 4 effects of age on mitos?

A

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
Q

What causes mPTP opening?

A

Increased mito Ca2+

Mito depolarisation

74
Q

What is the effect of mPTP opening?

A

H+ efflux - loss of H+ gradient
Decreased ATP production
Cell death

75
Q

What happens to fissioned mitos?

A

Fusion or mitophagy

76
Q

What is the physiological role of PINK1?

A

Regulates mito Ca2+ efflux - via IMM Ca2+/Na+ exchanger

77
Q

What is the effect of PINK1 deficiency?

A

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
Q

How do excess fission and fusion affect synapses?

A

Decreased ATP at synapse

79
Q

Which mitochondrial process are PINK1 and parkin involved in?

A

Mitophagy

80
Q

Name 7 mechanisms of mitochondrial quality control

A 
Mito chaperones
Mito proteases
Cytoplasmic UPS
mtUPR
Mitochondria derived vesicles (MDRs)
Mitophagy
Apoptosis
81
Q

What is the role of mitochondrial chaperones?

A

Fold protein once inside mito

82
Q

What is the role of mitochondrial proteases?

A

Break down improperly-folded proteins

83
Q

What is the role of cytoplasmic UPS?

A

Ubiquitinates faulty proteins

84
Q

What is the role of mtUPR?

A

Damaged mito protein causes signal to nucleus - increases transcription of chaperones and proteases

85
Q

What are mitochondria derived vesicles (MDRs)?

A

Damaged proteins cluster - form vesicles budding off mitos

Fuse with lysosome - degraded

86
Q

What type of parkin mutation increases PD risk?

A

Autosomal recessive

Loss-of-function

87
Q

What is the role of parkin in mitophagy?

A

Recruited to damaged mitos

E3 ubiquitin ligase - tags proteins for degradation with ubiquitin

88
Q

What type of PINK1 mutation increases PD risk?

A

Autosomal recessive

Loss-of-function

89
Q

How do PINK1 and parkin cause mitophagy?

A

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
Q

A mutation in which gene causes juvenile Parkinsonism with additional pyramidal signs?

A

Fbxo7

91
Q

What is the role of Fbxo7?

A

Facilitates parkin-mediated Mfn1 ubiquitination

May recruit parkin to mitos

92
Q

What is required for Fbxo7 translocation to mitos?

A

PINK1

NEUR0010 (9 decks)

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