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[MBD] NoNa > Neurodegenerative Diseases > Flashcards

Neurodegenerative Diseases Flashcards

1
Q

Define Neurodegeneration

A

Neurodegeneration = The progressive loss of neurons

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2
Q

What are neurodegenerative diseases ?

A

Neurodegenerative disease = Any disease caused by neurodegeneration (progressive loss of neurons)

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3
Q

Neurodegeneration affects which neurones?

When does Neurodegeneration begin?

A
  • CNS neurones/PNS neurones/Both

- Associated with ageing(=idiopathic), but can be childhood/from birth(=monogenic genetic mutation)

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4
Q

What are the different causes based on age of onset ?

A

Childhood(Rare). Earlier age of onset - Genetic contribution

Later age of onset - sporadic/idiopathic(unknown cause)cause

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5
Q

What are some examples of Neurodegenerative diseases?

A
  • Alzheimers - CNS
  • Huntingtons (purely monogenic disease) - CNS
  • Parkinsons - CNS
  • Motor Neurone disease (ALS) - PNS
  • Multiple sclerosis - CNS
  • Spinocerebellar ataxia - CNS (some PNS) - cerebellum + spinal cord
  • Spinal muscular atrophy - CNS
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6
Q

Why are neurodegenerative diseases highly heterogeneous ?

A

Highly heterogeneous - varying presentation.
Bc many are umbrella terms

  1. Overlapping phenotypes but distinct genetic causes
    E.g -
    SCA has 25 diff. types of mutations in different genes = cause diff. types of this condition

2.Inherently pleiotropic:
Symptoms manifest differently in different people

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7
Q

What pattern do neurodegenerative diseases follow ?

A

1.Molecular impairment somewhere within the cell

  1. Decreased transmission at synapse
    - Most likely at axon terminal, rather than dendrite
  2. Dying back of neurites - At the synapse (Axons and or dendrites) - progress towards cell body
  3. Cell death

The distance between the nucleus and the synaptic terminal is a weak point because things need to be transported a long way. - e.g. proteins are made in the nucleus, then must be transported to synaptic terminal - e.g. PNS motor neurone leaving spinal cord to big toe (1m distance)
= “Achilles heel “ = weak point in any neurone

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8
Q

What is the “Achilles heel” (weak point) in any neurone?

A

The distance between the nucleus and the synaptic terminal is a weak point because things need to be transported a long way. - e.g. proteins are made in the nucleus, then must be transported to synaptic terminal - e.g. PNS motor neurone leaving spinal cord to big toe (1m distance)
= “Achilles heel “ = weak point in any neurone

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9
Q

What are some common features of neurodegenerative diseases ?

A
  1. Protein aggregation (Proteinopathies )
  2. Lysosomal dysfunction . Lysosome = degradation
  3. Mitochondrial dysfunction
  4. Activated glia = neuroinflammation
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10
Q

What are the clinical challenges and research difficulties of neurodegenerative diseases ?

A

Neurodegenerative diseases rarely manifest overt (obvious) signs and symptoms until long after neurodegeneration has begun.

Early treatment is impossible without early diagnosis.

For CNS disorders, studying the affected tissue is v. difficult until death - brain tissue sample only at postmortem = not helpful to understand cause bc mess

Drugs to treat a condition that has already progressed a long way? Already dead neurones.

Neurodegenerative diseases are all incurable

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11
Q

What is the most common neurodegenerative disease+dementia ?

A

Alzheimer’s Disease

Onset is usually >65 years of age

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12
Q

What is dementia ?

A

Dementia = Decline in memory + other cognitive functions that impair quality of life

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13
Q

Normal ageing leads to …….

A

Gradual decline in normal cognition, gradual personality changes

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14
Q

Normal cognitive lapses vs Alzheimer’s cognitive lapses

A

Normal cognitive lapses:

  • lose keys
  • forget a name
  • normal mood changes
  • gradual personality change

Alzheimer’s cognitive lapses:

  • lost in own neighbourhood
  • not recognise family member
  • strong irrational mood changes
  • sudden personality change
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15
Q

What are pathological hallmarks ?

A

Pathological hallmarks are clear signs which indicate disease

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16
Q

Describe the pathological hallmarks of Alzheimer’s disease

A 
1.Brain shrinkage
Shrinkage of hippocampus 
Enlargement of ventricles
Cortex shrinks
Deeper sulci
Lack of ability to form memories

2.Proteinopathies = protein aggregation
Amyloid plaques:
-Extracellular protein aggregates, round bodies
-Enriched in A beta peptides
Neurofibrillary tangles/Tau tangles/Paired helical filaments:
-Intracellular protein aggregates
-Enriched in Tau protein

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17
Q

What is A beta peptide and how does it form Amyloid plaques ?

A

APP (amyloid beta precursor protein) TM protein is cleaved by proteases to form A beta peptide.

Cleavage by Beta-Secretase and then gamma-secretase and this releases the A beta fragment which accumulates forming the Amyloid plaques outside the cell

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18
Q

What can cause rare early onset forms of Alzheimer’s?

A

Mutations in proteins involved in A beta peptide processing :

APP
PSEN1
PSEN2

PSENs are both components of gamma-secretase. Mutation in second enzyme = can’t make the amyloid plaque

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19
Q

Amyloid Hypothesis of Alzheimer’s Disease =

A

Amyloid Hypothesis of Alzheimer’s Disease = It is the production of Abeta and/or production of Amyloid plaques that causes Alzheimer’s disease

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20
Q

What is Tau and what can this protein cause ?

A

Tau = Intracellular protein, normally binds microtubules in axons

Pathological process: Tau is hyperphosphorylated by kinases.serine,tyrosine which displaces Tau from microtubules, Causes:

  • Tangles (aggregates to form tangles)
  • Destabilisises Microtubules
21
Q

What is the importance of microtubules in neurites ?

A

Neurites are projections from the cell body of a neuron

In post-mitotic cells, microtubules have 3 roles:

  • Structure/Shape of cell
  • Positioning of organelles
  • Motorways for transporting vesicular cargo (proteins/lipids) b/w organelles/across cell

The distance between axon terminal and nucleus=Weak point.
Loss of microtubules = loss of motorway function to move substances across cell from nucleus to axon terminal

22
Q

Outline the Tau hypothesis

A

In late onset AD, neurofibrillary tangles are:

  • Seen before amyloid plaques
  • Well correlated with cell death + disease progression

Advanced AD = Lot of Tau protein. Early stage = not much Tau.
Where cell death is correlates with regions of cognition affected

This therefore suggests that Tau is upstream of A beta = Tau Hypothesis - Effects in Tau cause effects in Abeta

23
Q

Other risk factors for Alzeihmers Disease

A

Down syndrome (APP gene is on chromosome 21)

Gender (more common in women)

High Bp ,Cardiovascular disease, Diabetes - bad general health

Low education. education = cognitive reserves

Head injury (trauma)

Smoking + drinking

Genetic (rare, APOE gene status)

24
Q

What is Parkinson’s + Parkinson’s symptoms?

A

Parkinson’s = Movement disorder with 4 cardinal features:

  1. Resting tremor
  2. Bradykinesia (slow movement)
  3. Rigidity
  4. Postural instability (falling over = fracture bones - dangerous)
25
Q

What are the non-motor symptoms?

A 
Depression and Anxiety 
Loss of smell
Sleep disorders
Constipation 
Dementia 
Other psychiatric complications
26
Q

Outline the pathological hallmarks of Parkinson’s disease

A

1.Loss of dopaminergic neurons of the substantia nigra (neurons that produce the neurotransmitter dopamine)
Substantia nigra = Part of the basal ganglia in the midbrain, dark region (neuromelanin).
PD also affects other brain regions = other symptoms

2.Proteinopathy
Lewy bodies
Intracellular protein aggregates
Enriched in alpha-synuclein protein
Normal role of alpha-synuclein is poorly understood -involved in neurotransmitter release
Lewy bodies are not pathogenic but an increase in alpha-synuclein is.

27
Q

What categories of PD can have genetic causes ?

3 categories of gene mutations cause PD:

A
  1. Early/juvenile onset recessive mitochondrial conditions - autosomal recessive mutation
  2. Late/later onset autosomal dominant PD
  3. Mutations that cause PD plus conditions - rare - Parkinson’s + complications
28
Q

Outline the early onset mitochondrial PD

A
  • Mitochondira have a finite life span due to oxidative stress (=damage)
  • Damaged mitochondria are removed by mitophagy - engulf damaged mitochondria + target to lysosome to degrade + recycle
  • Loss of function mutations in 2 proteins central to activating mitophagy (PINK1/Parkin) cause Early Onset Parkinson’s Disease)
  • Mutations in >3 other genes linked to mitochondrial stress response impairment also linked to EO PD.
This PD (EOPD) is distinct from late-onset sporadic PD - diff progression, diff postmortem pathology
PINK1+Parkin mutations = neurodegeneration v. selective forsubstantia nigra
29
Q

Outline the gene mutations causing Late Onset Genetic PD

A

Some genetic causes found from kindred studies (like EO PD) but more limited, including:

SNCA (a-synuclein) gene amplification - DUPLICATION/ACTIVATING POINT MUTATION
-confirms that a-synuclein (Lewy body protein) is pathogenic
-mutation in gene encoding SNCA linked to genetic PD
⬆ alpha-synuclein causes PD

LRRK2 gain of function

VPS35 gain of function

GBA loss of function. dominant loss of function mutation. carriers of recessive mutation. if get both copies, they get Gaucher disease early in life - lysosomal storage disorder. = greater chance of having relatives w Parkinson’s (carriers of this mutation). If carrier of GBA mutation, you have 3-fold increased risk of getting PD

30
Q

How has GBA been linked to a-synuclein?

A

GBA encodes GCase (beta-glucoerebroisidase) = a lysosomal enzyme

a -synuclein is degraded in the lysosome via autophagy

31
Q

Describe what happens to the GCase enzyme in a healthy person

A

The GCase enzyme is trafficked into the lysosome from other organelles (The Golgi and ER). In the lysosome it is acts as the final stage of autophophy to degrade a-synuclein = no accumulation, no Lewy bodies, no PD

32
Q

In what way can PD affect lysosomes?

A

Consistently leads to disregulated autophagy.

Problems in autophagy will also lead to mitochondrial dysfunction-Mitophogy

33
Q

Describe what happens if an individual inherits a GCase mutation GBA gene mutation?

A

They will have less activity/expression of GCase. Less active GCase in the lysosome impairs the lysosome = cannot do the last step of autophagy = can’t degrade alpha-synuclein = a-synuclein accumulates = pathogenic Lewy bodies formation

34
Q

What happens if there is no GBA mutation but there is an increase in a-synucleins (due to sporadic PD/another mutation) ?

A

The excess a-synuclein will inhibit the translocation of GCase into the lysosome = impairs lysosome function = Lysosome cannot carry out autophagy = causes further increase in a-synuclein = Pathogenic feedforward loop.

Increased a-synuclein = cell death

35
Q

PD & Lysosomes

A
  • Other PD genes play roles in processes involving lysosomes
  • Consistently, autophagy is dysregulated in PD brains.
  • Problems in autophagy will also lead to mitochondrial dysfunction (↓ mitophagy) = damaged mitochondria aren’t removed but accumulate
  • Endocytic pathways are a big focus in PD research
36
Q

What gene found to be linked to Parkinsons disease was unexpected?

A

MAPT which encodes Tau as Tau = Alzheimer’s Disease protein.

Neurofibrillary tangles (NFTs) can be found in PD brains + in the same cells as Lewy bodies, just as found in healthy brains

More NFTs in brains of LRRK2 PD
Microtubules disruption long implicated in PD.

MAPT Tau mutations reduce ability of microtubules to transport vesicles from nucleus to synapse = weak point Achilles heel of cell = cell is more susceptible to additional insults

37
Q

1/3 of the risk of ………. PD comes from your genes

A

sporadic

38
Q

What are some risk factors ?

A 
Gender
Red hair
Head injury 
Not smoking/not consuming caffeine
Herbicides,pesticides,insecticides
Exposure to metal
General anaesthesia
39
Q

What is Neuroinflammation ?

A

Neuroinflammation = the activation of the immune system within the nervous system.
In the brain this means activation of microglia (+ astrocytes are also involved )

40
Q

What are reactive microglia and what changes happen ?

A

Microglia is activated to become reactive microglia

It becomes a Ameboid shape (irregular shape, arms removed)
More motile
Produces cytokines
Phagocytic (engulfs cellular debris + pathogens)

41
Q

How is neuroinflammation involved in neurodegeneration ?

A

Following neurotoxic insult to neurone, there is a dying/damaged neuron which will release factors (a-synuclein and other proteins)
This will activate the microglia which become reactive microglia, which will release neurotoxic factors (IL-1B, TNF-a, prostaglandins) and this will trigger more cell damage + cell death.
This will create a positive feed forward loop.
Neuroinflammation amplifies the effects of neurodegeneration

42
Q

What are the 2 types of reactive microglia?

A

Protective - protect neurones:

  • release Anti-inflammatory cytokines e.g. TGFBeta
  • Normal removal of unhealthy cells - homeostasis

Damaging - damage neurones:
-release pro-inflammatory cytokines e.g. IL-1, TNF-alpha
-Destroys pathogens etc
(damage to neurons = collateral damage )

43
Q

How does ageing affect the type of active microglia we have ?

A

Ageing induces a shift towards production of damaging reactive microglia due to changes in microglial gene expression
= Stimuli that shd cause protective reactive microglia end up producing damaging reactive microglia = Neuroinflammaging

44
Q

What are some other ways in which neuroinflammation triggers neurodegeneration

A

External trigger (e.g. Abeta triggers reactive microglia, pathogens, brain infection)
Environmental toxins
Pathogens
A-beta

Neuroinflammation can exacerbate neurodegeneration AND trigger neurodegeneration

45
Q

What are some evidence for neuroinflammation being the cause ?

A

Many Alzheimer’s risk factors cause raised levels of circulating inflammatory cytokines (smoking, high bp, cardiovascular disease, diabetes)

Circulating cytokines effects can cross the blood brain barrier + induce further inflammation within the brain

46
Q

What is the PD gut-to-brain theory ?

A
  • Lewy body pathology (alpha-synuclein aggregates) in the gut can often precede pathology in brain
  • Evidence that gut inflammation is sufficient to cause gut Lewy bodies
  • May spread to brain via the Vagus nerve, activating brain neuroinflammation

May be due to gut microbiota (there is Increased constipation in PD+increased inflammation + increased oxidative stress) that triggers alpha-synuclein spread up to the brain

Neuroinflammation = driving factor for PD. PD starts in gut + spreads to brain

47
Q

What other ways can ageing affect neurodegeneration?

A

Shortening of telomeres in adult stem cells = unable to replace dying neurones

Increased reactive oxygen species = ⬆ stress on neurones

Gene expression:
-Altered Wnt signalling is a big focus in AD + PD.
Wnts are neuroprotective (stop neurone death) + neuromodulatory (alter synapse strength=memory/cognition)
Wnt/beta-catenin is decreased in the adult brain.

Deregulated Wnt signalling causes developmental neurological conditions + geriatric neurological conditions.

48
Q

neurodegeneration is always accompanied by …………., and neuroinflammation itself can be a trigger of …………………

A

neuroinflammation

neurodegeneration

49
Q

Neurodegenerative diseases are all ……..

A

incurable

[MBD] NoNa (28 decks)

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