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Neurodegeneration Flashcards

1
Q

What are common pathological features of neurodegenerative diseases?

A 
Loss of neurones 
Late onset
Protein aggregation 
Progression with age
Genetic causes in at least some patients
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2
Q

What are the causes of HD,AD,PD,MND?

A

HD - HTT mutation

AD,PD, MND (some genetic causes but this only accounts for 10-15% of patients)

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3
Q

What are some common mechanisms of neurodegeneration that may exist?

A
  • Defective protein degradation systems

- Mitochondrial energetics defect

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4
Q

Name the onset for Alzheimer’s Disease Parkinson’s Disease Huntington’s Disease Multiple Sclerosis
Motor Neuron Disease Creutzfeldt Jacob Disease

A 
AD: 65+
PD: 55+
HD: 40+
MS: 30+
MND: 40+
CJD: 50+
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5
Q

What are the gender distribution of MS, MND, and PD?

A

PD: Men
MS: women
MND: men

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6
Q

What are some general common features about neurodegenerative diseases?

A
  • Associated with increased age
  • Family history is a risk factor
  • Each disease is predominantly associated with the loss of specific neuronal population
  • Pathology involves accumulation of specific protein aggregates
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7
Q

Which areas of the brain and what neurones are most affected in AD, PD, HD, and CJD?

A

AD: Hippocampus, entorhinal cortex (cholinergic)

PD: Substantia nigra (dopaminergic)

HD: Caudate nucleus (Gabanergic medium spiny neurons)

CJD: Cerebellum

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8
Q

What pathological features are in AD, PD, HD, and CJD respectively?

A

AD: Plaques/tangles
PD: Lewy bodies
HD: Intranuclear inclusions
CJD: plaques

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9
Q

TRUE or FALSE? In AD and HD, only the hippocampus/entorhinal and caudate nucleus are affected.

A

FALSE

Other areas are affected as well but not as much

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10
Q

What are the protein aggregates in AD, PD, HD, and Prion?

A

AD: beta- amyloid and tau
PD: alpha-synuclein
HD: Huntingtin
Prion: Prion protein

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11
Q

Where are the aggregates in AD, PD, HD, and Prion (in the cell)?

A

beta- amyloid extracellular

tau - intracellular

alpha-synuclein - intracellular

Huntingtin - intranuclear

Prion protein - extracellular

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12
Q

What are the gene mutations associated with AD?

A

APP gene mutations
PSEN1/2 gene mutations (2-5%)

APOE E4 allele (30%)`

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13
Q

what do APP and PSEN1/2 genes control?

A

beta- amyloid formation

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14
Q

What gene mutations are associated with PD?

A

8-10% GBA1 heterozygous mutations

2% LRRK2, PINK1, Parkin, SNCA

<1% SNCA alpha synuclein gene mutation

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15
Q

What gene mutations are associated with prion disease?

A

10-15% caused by mutations to PRPN (Prion) gene

small portion due to transmission by exposure to contaminated material

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16
Q

What is the amyloid cascade theory of AD?

A

proposes that plaque-related changes precede tangle-related changes and positions amyloid as central to the degeneration of AD.

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17
Q

What is APP’s role in alzheimer’s?

A
  1. APP is thought to help the neurone grow and repair after injury
  2. Usually when being broken down alpha and gamma secretase break it
  3. If beta secretase cuts it instead of alpha it makes a monomer called amyloid beta (sticky and insolube) –> form plaques
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18
Q

What are the genetic mutations that are related to APP’s role in AD and how do they do it?

A

PSEN1 and PSEN2 code for gamma secretase which might cleave in the wrong place and make the protein stickier

APP mutations

Increased APP due to Down’s

Sporadic load can be worsened by other factors that lead to beta amyloid generation (e.g. by increasing their half lives)

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19
Q

How common are APP mutations in AD?

A

Very rare

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20
Q

How common are Tau mutations in AD?

A

Non-existant

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21
Q

Where do we see tau mutations?

A

frontotemporal lobular dementia

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22
Q

How common are SNCA (synuclein) mutations in PD?

A

Very rare

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23
Q

How common are PRPN mutations in CJD?

A

Rare

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24
Q

How common are HTT CAG repeats in HD?

A

99%

25
Q

What does the fact that mutations of the gene encoding the protein that aggregates cause a rare form of the disease imply?

A

it implies changes to the protein that aggregates can cause disease (show how relevant aggregates are to the disease not just junk proteins)

26
Q

Describe the pathophysiology of CJD

A

PRPN –> PrP –> PrPsc –> plaques –> degeneration of cerebellum –> cjd

27
Q

Describe the pathophysiology of SNCA caused PD

A

SNCA mutation –> alpha synuclein –> alpha synuclein aggregation –> lewy bodies –> loss of dopaminergic neurones in SN –> PD

28
Q

Describe the pathophysiology of APP caused AD

A

APP mutation–> beta amyloid –> Abeta peptide aggregation –> plaques –> degeneration of hippocampus –> AD

29
Q

How do the mutated version of the proteins differ from the WT versions?

A

They have more beta sheets

30
Q

What effect does the change in structure of the mutated proteins have on their molecular function?

A

they wanna make more H bonds with everything

they are resistant to degradation

31
Q

What are factors that may influence the presence of aggregates?

A

too much bad protein synthesized

stresses which cause the protein to unwind and change structure

problems with protein degradation pathways

32
Q

What are the 3 methods of protein degradation?

A

Ubiquitin proteosome system

Lysosome (chaperone mediated autophagy)

Macroautophagy

33
Q

How does the lysosome degrade things?

A

Autophagy (chaperone mediated)

Macroautophagy

Microautophagy

34
Q

What are types of protein degradation defects in neurodegenerative disease?

A

lysosomal pathway defects

proteosomal pathway defects

35
Q

What are lysozomal pathway defects and how do they replate to neurodegenerative diseases?

A

AD - decrease in lysosome content in AD brains

PD - various genetic mutations that cause PD influence lysosomal function GBA, ATP13A2 mutations
- decrease in lysosomal content in PD brains

36
Q

What are proteosome pathway defects and how do they replate to neurodegenerative diseases?

A

HD - proteosomal defects in HD brain

PD - inhibitors of the proteasome cause degeneration of dopaminergic neurons in animal models
- Parkin mutations cause PD, and it ubiquitinates proteins for protesomal degradation

37
Q

TRUE or FALSE? Protein aggregates seem to increase homogenously through the brain in neurodegenerative disease progression

A

FALSE

Aggregates appear to spread across the brain as disease progresses

38
Q

How do aggregates in Alzheimer’s disease progress?

A

Beta amyloid: from the neocortex and hippocampus –> allocortex - olfactory —> subcortical region (top down)

Tau: Brain stem –> entorhinal cortex –> amygdala –> neocortex (down up)

39
Q

How do aggregates in PD progress?

A

Brain stem —> cortical regions

40
Q

TRUE or FALSE? The symptoms of PD (other than the characteristic motor problems) vary significantly between people?

A

TRUE

41
Q

What symptoms might you get in PD prodrome?

A

depression, loss of smell, constipation, anxiety

42
Q

Name 3 prion diseases

A

Creutzfelt Jacob disease
Scrapie
Bovine spongiform encephalopathy

43
Q

What were the pieces of evidence which suggested prion diseases were passed on by exposure to contaminated materials?

A

Kuru- cannibals in Papua New Guinea
People who needed growth hormon in the 70/80s
Dura mater and corneal grafts
surgical equipment used in CNS operations
people who got mad cow disease
blood transfusions

44
Q

Explain the consept of permissive templating

A

If the misfolded protein is there it likes to hydrogen bond with similar (normal ) proteins and cause them to refold into pathogenic forms –> aggregation

45
Q

What is the proposed mechanism of PrPsc accumulation?

A
  1. some initial cause changes normal PrPc into PrPsc, inocculation, or PRPN mutation
  2. This aggregate leaves one neuron and enters its neighbour
  3. The PrPsc interact with PrPc and convert them to PrPsc (more beta-sheet structure)
  4. Amplification: This repeats itself
  5. The PrPsc accumulate
  6. Aggregates may leave cell and enter neighbour to repeat event
  7. plaque formation and cell death
46
Q

What is the evidence that prion, tau, and alpha-synuclein protein aggregates can pass between neurones?

A

Tau and alpha-synuclein are realeased by neuron in culture and are found in CSF

Injected protein aggregates in the mouse brain lead to spread of aggragates in the brain, loss of neuones, and clinical symptoms

If the mice or neurons do not expres the normal tau, prion, or synuclein protein the transmission of aggregates do not proceed

47
Q

Why do proteins aggregate in AD and PD?

A

mutation of protein - rare

exposure to protein - no evidence

spontaneous aggregation - maybe due to aging as systems become less efficient

too much protein made

too little degradation

48
Q

Which systems becoming less efficient with age may leed to protein aggregates?

A

more misfolding due to increased stresses

less refolding

less degradation

49
Q

When is too much protein synthesized (leading to PD)?

A

can be caused when there is an extra copy of the SNCA gene (triplication) - early onset

50
Q

What is the evidence that mitohondrial respiratory chain defects are involved in PD pathogenesis?

A

MPTP (complex 1 inhibitor) induced parkinsonism

Complex 1 activity id decreased in PD SN

PINK1 and parkin (rare: genes mutated that cause PD) control the degradation of damaged mitochondria by autophagy

GBA1 mutations (risk factor for PD) lead to secondary MRC defects

Recent- mitochondrial dysfunction may link various genetic causes of PD

51
Q

What is the mechanism of MPTP toxicity?

A
  1. MPTP not charged so crosses the BBB and converted to MPP+ by MAOb in the mitochondria of astrocytes.
  2. Then it is exported out of the astrocyte
  3. Dopaminergic neurons have dopamine transporter which MPP (dopamine analog) uses to enter –> cause mitochondrial complex 1 inhibition
  4. neuron death
52
Q

Explain the process of mitophagy

A

As mt divide there are small bits of the mt which come off

PINK1 and parkin prevent fusion if there is damage in those bits and then they get engulfed by autophagy

Otherwise, with the help of mitofusin and Opa1, the bits of mitochondria fuse

53
Q

What pathway has a recent paper suggested realting PD and mitochondrial dysfunciton.

A

Various PD causes lead to mt stress–> oxidises dopamine –> lysosomal dysfunction and decreased GCase –> increased alpha synuclein

lysosomal dysfunction also leads to further mt dysfunction and thus more mt oxidative stress

54
Q

What gene codes for GCase?

A

GBA1

55
Q

What mt defects are found in AD?

A
  • Complex IV defect detected in AD brains

- Beta amyloid can inhibit the MRC

56
Q

How do mt defects relate to HD?

A
  • Complex II inhibitor 3 nitroproprionic acid can induce a HD like disease (contaminant of sugar cane)
  • Complex II/III defect detected in HD brain,
57
Q

What is the unfolded protein response?

A
  1. In the ER, if the protein is misfolded Bip chaperone targets it
  2. If you have lots of misfolds Bip which is usually associated with IRE or PERK come off them and IRE and PERK come together (not with each other ) to stop misfolding.
  3. If this doesn’t work –> cell death
58
Q

How do IRE and PERK try to stop misfolding?

A

Decreasing translation

Increasing protein degradation

Increasing protein folding

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