Neurodegenerative diseases

Question 1

What is meant by sporadic PD or AD?

Answer 1

Basically, sporadic means that there is not a genetic cause (I think) -A disease occuring randomly with no known cause.

For AD: The familial form is due to mutations in three major genes (amyloid precursor protein (APP) gene, presenilin1 (PSEN1) gene and presenilin 2 (PSEN2) gene). In contrast, many genetic and environmental factors may contribute to determining the sporadic AD form.

Question 2

What is meant by neurodegeneration and name some characteristics of neurodegenerative disease

Answer 2

A progressive loss of neurones

Neurodegenerative diseases

can begin at any stage of life (but usually in old age),
affect PNS or CNS
are highly heterogeneous
usually an early onset means that it is a genetic disease

Question 3

Name the most common and second most common neurodegenerative diseases

Answer 3

Alzheimer’s
Parkinson’s

Question 4

Name one neurodegenerative (not NTD) disease that is onset from birth

Answer 4

Spinal muscular atrophy, all other main neurodegenerative diseases begin from around 40

Question 5

Describe why neurodegenerative diseases tend to be very heterogeneous

Answer 5

Some disease names are actually umbrella terms of conditions

Diseases may have overlapping phenotypes but with different causes (like different mutations)

Question 6

Name some common molecular features of neurodegenerative diseases

Answer 6

molecular impairment somewhere in the cell
decreased transmission usually at axon terminal synapses
death of neurites and this moves towards the cell body
cell death
Also protein aggregation (proteinopathies), lysosomal dysfunction, mitochondrial dysfunction and inflammation via activation of glia

Question 7

Is Alzheimer’s disease a normal part of aging since it is so prevalent?

Answer 7

NO

Question 7

Define dementia

Answer 7

A decline in memory and other cognitive functions that impairs quality of life

Question 7

Why are neurodegenerative diseases particularly difficult to treat?

Answer 7

Neurodegenerative diseases rarely manifest overt signs and symptoms until long after the neurodegeneration has begun

so early treatment is hard if the neurones are already dead
Also, you cannot take a biopsy of the brain and they are difficult to understand post-mortem

Question 7

What is meant by the Achilles heel of a neuron?

Answer 7

The distance between the axon terminal and its nucleus - this is as you need to move intracellular components a long way to maintain parts of the neurone that are far from the nucleus

Question 8

Name some of the symptoms of dementia

Answer 8

are distinct from normal cognitive lapses (so it is not like losing keys, it is more like getting lost in your own neighbourhood)

distinct memory loss like not recognising a family member
strong and irrational changes of mood unlike regular mood changes
sudden changes in personality distinct from gradual changes in a healthy person

Question 8

Describe the onset of Alzheimer’s

Answer 8

Is usually greater than 65 years old but 10% of people have ealry onset meaning that it starts from around 30 onwards

10% of all people over 65 have Alzheimer’s
50% of all people over 85 have Alzheimer’s

Question 8

What is PSEN 1 and 2?

Answer 8

Presenilin 1 and 2 (like pre-senile) and they are both components of γ-secretase

Question 9

Name the 2 proteinopathies found in Alzheimer’s disease

Answer 9

Are both protein aggregates

Amyloid plaques (round bodies that sit outside the cell, enriched by the peptide A beta)
Neurofibrillary tangles (within cell, are enriched in Tau protein)

Question 9

Name the pathological hallmarks of Alzheimer’s disease

Answer 9

Brain shrinkage! Especially hippocampus
Proteinopathies (aggregations of proteins)

Question 9

What is Aβ? In the context of Alzheimer’s

Answer 9

This is a peptide produced by the cleavage of a transmembrane protein called APP (amyloid beta precursor protein) by proteases.

Question 10

Name the 3 genes that cause early onset Alzheimer’s

Answer 10

APP
PSEN1
PSEN2
These are all involved in the processing of APP to Aβ

Question 10

What is the amyloid hypothesis?

Answer 10

The production of Aβ and amyloid plaques is the major cause of Alzheimer’s

Question 10

Name the 2 proteases in the cleavage of Aβ

Answer 10

β-secretase and then γ-secretase forms Aβ which accumulates and forms plaques outside of the cell

Question 11

Describe the normal function of Tau, and what happens to it when pathological?

Answer 11

Tau normally binds to microtubules in axons

But can become hyperphosphorylated meaning that it tangles and destabilises microtubules!

Question 12

What are the 3 roles of the microtubules?

Answer 12

structure and shape of cell
positioning of organelles
motorways for vesicular cargo

Question 12

So what 2 things cause toxicity due to pathological Tau?

Answer 12

The tangling of the Tau protein itself as well as the destabilisation of the microtubules

Question 13

Discuss the evidence for the amyloid vs the Tau hypothesis

Answer 13

is controversial
probably is more evidence for amyloid, but therapies based on inhibiting Aβ aggregation so far have not worked!
tangles and plaques may both be not pathogenic, and may be by-standers or may even be protective, there is evidence that the big aggregates are not pathogenic, but instead the smaller oligomers

Question 13

In typical, late onset, AD, discuss how the disease manifests - what happens on the molecular level

Answer 13

Neurofibrillary tangles are seen before amyloid plaques

these are well correlated with cell death and progression of the disease

Question 13

What is the Tau hypothesis?

Answer 13

This suggests that Tau is upstream of Aβ, so Tau is the main cause

evidence is as in late onset (normal, not genetic forms of) AD, Tau is present before amyloid plaques are

Question 14

Name some other risk factors for AD

Answer 14

Down’s syndrome (APP gene is on chromosome 21)
More common in women
High BP, CVS disease, diabetes
Low education
Head injury
Smoking and drinking

Question 14

Describe the onset of Parkinson’s disease

Answer 14

Usually 60-65 but 10% start before 45

Question 15

Describe the genetic contributions to Alzheimer’s between early onset and late (regular onset)

Answer 15

(I think)

Early onset tends is usually genetic but late onset only has a small genetic contribution, the APOE gene status is most significant

Question 16

Name the 4 cardinal features of Parkinson’s

Answer 16

resting tremor (hands shake when not moving then goes when they move the hands)
bradykinesia (slow movement)
rigidity
postural instability (falling over, comes last)

Question 16

Describe the lifetime risk of PD between men and women

Answer 16

Men - 2%

Women 1.3%

Question 17

Describe how these features in PD progress

Answer 17

the resting tremor starts in one hand then spreads over to the other hand then the feet and then other parts of the body, also the last feature of Parkinson’s to come is postural instability - patients fall over and may break bones

younger patients get resting tremor first
older patients may start off with the bradykinesia and rigidity

Question 18

Name some of the non-motor symptoms of Parkinson’s

Answer 18

depression and anxiety
loss of smell
sleep disorders
constipation
other psychiatric complications (less common)
dementia (less common)

Question 19

One of the hallmarks of Parkinson’s is a loss of ______________ergic neurones of the ___________ ____________ in the brain

Answer 19

Loss of dopaminergic neurones of the substantia nigra of the brain

Question 20

What is the normal role of the protein that aggregates in PD?

Answer 20

The role of α-synuclein is not fully understood but it is thought to be involved in the release of neurotransmitters

Question 20

Describe how the appearance of this main brain region changes by eye in PD

Answer 20

substantia nigra means dark substance because the dopaminergic neurones of the substantia nigra produce neuromelanin which is dark, so in a brain with Parkinson’s these dark stripes are lost

Question 20

PD is a proteinopathy, describe what protein aggregates and the name of these aggregates formed

Answer 20

Intracellular protein α-synuclein protein aggregates to form Lewis bodies

Question 20

So are these aggregates pathogenic in PD?

Answer 20

No, it is thought that Lewis bodies are not pathogenic, but that the increase in α-synuclein is pathogenic

Question 21

10% of PD cases have a clear genetic cause, name the 3 rough categories

Answer 21

Early/juvenile-onset recessive mitochondrial conditions
Later-onset is usually autosomal dominant mutations
Mutations that cause a more severe PD with additional symptoms (are very rare)

Question 21

Why do mitochondria have a limited lifespan?

Answer 21

Due to oxidative stress as they damage themselves

Question 22

What is mitophagy and why is it important?

Answer 22

This is the removal of damaged mitochondria so that they do not damage the cell with reactive oxygen species (so is autophagy of mitochondria)

Question 23

So, name the 2 genes that when mutated can cause early-onset PD and explain how this happens

Answer 23

mutations in PINK1 and Parkin cause early onset PD
these genes are involved in the autophagy of damaged mitochondria (is called mitophagy)

Question 23

Explain a limitation of this finding (that we know 2 genes that when mutated can cause early-onset PD)

Answer 23

The neurodegeneration in PD in these mutations is distinct from late-onset PD and is almost a whole different disease (remember that PD is an umbrella term)

Question 24

Name 4 some genetic causes that we have found for late-onset PD

Answer 24

SNCA (α-synuclein) gene amplification (mutation or duplication), this confirms that α-synuclein is pathogenic

LRRK2 and VPS35 gain of function

GBA loss of function

Question 24

Explain the function of the GBA gene - what does it encode?

Answer 24

GBA encodes GCase

Question 24

Of the 4 mutations in late onset PD, describe the outlier

Answer 24

This is the GBA mutation

it is loss of function
if you have one copy you may have PD (3x risk)
if you have 2 copies you have a far worse disease (so one copy, means you have PD and you are a carrier for this worse disease)

Question 25

So explain how a loss of function mutation in this gene (gba) increases your risk of PD

Answer 25

α-synuclein degradation in the lysosome one of the last steps in autophagy of mitochondria (mitophagy)

GBA encodes GCase which is a lysosomal enzyme that helps to degrade α-synuclein in the lysosome, so loss of function of GCase causes a buildup of α-synuclein!

Question 26

If there were to be no GCase mutation (so in GBA) but there is a buildup of α-synuclein, what happens pathologically?

Answer 26

The buildup of α-synuclein can inhibit the entry of GCase into the lysosome for degradation of α-synuclein!!

Question 27

So explain why the mechanism for PD by a buildup of α-synuclein has been described as a pathogenic feed-forward loop

Answer 27

Increased α-synuclein causes decreased GCase function (by inhibiting transport into lysosome) which decreases lysosomal function which means that there is more α-synuclein

both decreased lysosomal function and increased α-synuclein can cause cell death

Question 28

Describe where other mutations can occur to cause PD

Answer 28

genes involved in lysosomal function meaning that autophagy (mitophagy) is dysregulated in PD brains

Question 29

GWAS of sporadic PD

Answer 29

there are other genes that may add risk %

Question 30

Why is the finding of MAPT gene discovered on a GWAS of sporadic PD interesting?

Answer 30

MAPT codes for Tau which is one of the 2 proteins involved in Alzheimer’s!

Neurofibrillary tangles are found in PD brains and even in the same as Lewy bodies but not any great extent - however, more tangles are found in brains of people with LRRK2 mutation PD! This means that microtubule disruption may be implicated in PD

So Tau mutation may not be enough for PD but increase risk

Question 31

Name some other risk factors for PD

Answer 31

gender (more common in men)
red hair
head injury
NOT smoking and NOT consuming caffeine
herbicides, pesticides, insecticides
exposure to metals
general anaesthesia

Question 32

What is neuroinflammation?

Answer 32

The activation of the nervous system’s immune system - so mainly microglia (but also astrocytes)

Question 33

Describe a reactive microglia

Answer 33

This is an activated microglia and it will be more mobile, have an amoeboid shape (less long arms), will produce cytokines and will eventually become phagocytic

Question 34

Describe how neuroinflammation in neurodegenerative disorders occurs

Answer 34

Neuronal damage or death causes release of microglial activators such as α-synuclein and other proteins. So microglia become active (reactive) and will release neurotoxic factors that cause the neurone cell death.

this forms another positive feed-forward cycle

Question 35

Name some neurotoxic factors released by reactive microglia

Answer 35

IL-1B, TNF-α, prostaglandins

Question 36

Describe the 2 different types/functions of microglia - what does each secrete

Answer 36

When microglia become reactive microglia they become wither protective or damaging

protective - anti-inflammatory mediators like TGF beta, their role is in the removal of unhealthy cells

damaging - pro-inflammatory like IL-1 and TNFα, these destroy a lot more

Question 37

Why would we even have this damaging type of reactive microglia?

Answer 37

As sometimes we need to destroy a pathogen and neuronal damage is collateral damage (a price worth paying)

Question 38

Explain the effects of ageing on neuroinflammation

Answer 38

Ageing induces a shift towards a production of the damaging forms of microglia due to changes in gene expression, so stimuli that should be activating protective functions actually stimulate damaging microglia

we call this neuroinflammaging

Question 39

So describe how an external trigger can cause neurodegeneration

Answer 39

The neuroinflammation may be the actual cause of the damage (not the damage causing the inflammation) and so an external trigger such as Aβ, environmental toxins or pathogens may feed into this cycle

Question 40

Explain how some of the risk factors for AD (smoking, high BP, diabetes, CVS disease) are thought to cause AD

Answer 40

Many of the risk factors for AD discussed before cause raised levels of circulating inflammatory cytokines that can cause this cycle. For example:

CVS disease
High BP
Diabetes
Smoking
And these circulating cytokines can cross the BBB but we do not know if this is enough to CAUSE AD

Question 41

Describe how PD may be due to external triggers - this is a new theory

Answer 41

In PD, we are now understanding that neuroinflammation may be a driving factor in PD. We now think that Lewy body pathology in the gut may lead to PD in the brain - so gut inflammation may cause Lewy bodies which can potentially spread via the VAGUS nerve to the brain!

so gut microbiota may have a role in PD, may also be why PD can cause constipation

Question 42

As well as neuroinflammation, name some ways that ageing can effect neurodegeneration

Answer 42

Shortening of the telomeres in stem cells means that it is harder to replace dying neurones
Increased ROS (reactive oxygen species)
Changes in gene expression (like altered Wnt signalling)

Question 43

Describe how changes in gene expression to Wnt signalling may affect AD and PD

Answer 43

Wnt signalling is important in AD and PD research, Wnts are neuroprotective and can alter the strength of synapses (are neuromodulative) and so they have a role in cognition. Wnt/Beta caterin is decreased in adult brain (these are Wnt ligands)