Neurodegenerative Diseases

Question 1

What are the basic characteristics of neurodegenerative diseases?

Answer 1

Affect the CNS or PNS (or both)
Begin at any stage of life
- The most common ones are associated with ageing
- Rarer types of neurodegenerative disease start in childhood or even from birth
- Earlier age of onset = greater genetic contribution
- Later age of onset = more likely a sporadic (or idiopathic) disease

Question 2

Name 7 neurodegenerative diseases, their age of onset and whether they affect the PNS or CNS?

Answer 2

Alzheimer’s disease (AD)
~65 and over
CNS

Huntington’s disease (HD)
~40
CNS

Parkinson’s disease (PD)
60 to 65 (and over)
CNS

Motor Neurone disease
(Amyotrophic lateral sclerosis – ALS)
40-70
PNS

Multiple sclerosis (MS)
20-50
CNS

Spinocerebellar ataxia (SCA)
~30-40
CNS (some PNS)

Spinal muscular atrophy (SMA)
From birth
PNS

Question 3

How are neurodegenerative diseases heterogeneous?

Answer 3

Neurodegenerative diseases are highly heterogeneous
- Some disease names are really umbrella terms
Conditions with overlapping phenotypes, but distinct causes (e.g. at least 25 types of SCA from mutations in different genes)
- Some diseases are inherently pleiotropic
Symptoms manifest differently in different people
(e.g. Parkinson’s disease symptoms unique to individual)

Question 4

What are the common neuronal features of NDs?

Answer 4

Many follow a similar pattern:
- Molecular impairment somewhere in the cell
- Decreased transmission at synapse
- “Dying back” of neurites (axons and/or dendrites)
- Cell death
Distance between axon terminal and nucleus= a neuron’s “Achilles heel”

Question 5

What are the common molecular features of NDs?

Answer 5

Frequently involve:

- Protein aggregation (“proteinopathies”)
- Lysosomal dysfunction
- Mitochondrial dysfunction
- Associated inflammation via activation of glia

Question 6

What are the clinical difficulties of NDs?

Answer 6

Neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has begun
- Early treatment is impossible without early diagnosis
- Therapeutic challenge is considerable
For CNS disorders, studies of affected tissue is very difficult until death
- Advanced brain pathology is of little help to understanding the causes
Neurodegenerative diseases remain incurable

Question 7

What is dementia?

Answer 7

A decline in memory and other cognitive functions that impair quality of life
Impairments in dementia are distinct from “normal” cognitive lapses, e.g. not recognising family members and strong changes in personality is not the same as losing keys or forgetting someone’s name
Normal ageing = gradual decline in normal cognition, gradual changes in personality

Question 8

What are the pathological hallmarks of Alzheimers’s?

Answer 8

Brain shrinkage
Proteinopathies
Amyloid plaques
	- Extracellular protein aggregates
	- Enriched in Aβ peptides
Neurofibrillary tangles
	- Also called paired helical filaments
	- Intracellular protein aggregates
Enriched in Tau protein

Question 9

What are Aβ and APP?

Answer 9

Aβ peptide is cleaved from a transmembrane protein called amyloid-beta precursor protein (APP) by proteases
First by beta-secretase, then by gamma-secretase and the product accumulates as amyloid plaque outside of the cell

Question 10

What is the amyloid hypothesis?

Answer 10

Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s
- APP
- PSEN1 (Presenilin-1)
- PSEN2 (Presenilin-2) both a components of y-secretase
Since early 1990’s “Amyloid hypothesis of AD”, which states that Aβ and/or amyloid plaques are the cause of AD
However therapies based on inhibiting Aβ aggregation so far haven’t worked

Question 11

What is Tau?

Answer 11

Tau normally binds to microtubules in axons
Hyperphosphorylated tau is displaced causing:
- Tangles
- Destabilised microtubules when Tau detaches from them

Question 12

Why are microtubules important in neurites?

Answer 12

In all post-mitotic cells, microtubules have 3 main roles:

1. Structure/shape of cell
2. Positioning of organelles
3. Motorways for transporting vesicular cargo

Question 13

What is the Tau hypothesis?

Answer 13

In typical late onset AD (i.e. not genetic forms of AD), neurofibrillary tangles are:
- Seen before amyloid plaques
- Well correlated with cell death and progression
Suggests Tau is upstream Aβ = Tau hypothesis

Question 14

What are other risk factors of AD?

Answer 14

Down syndrome (APP is on chromosome 21)
Gender (more common in women)
High BP, Cardiovascular disease, Diabetes
Low education
Head injury
Smoking and drinking
Only a small genetic risk contribution for late-onset AD (APOE gene status most significant)

Question 15

What are the cardinal features of Parkinson’s disease?

Answer 15

A movement disorder, with four ‘cardinal’ features:

1. Resting tremor
2. Bradykinesia (slow movement)
3. Rigidity
4. Postural instability (fall over)

Question 16

What are the non-motor symptoms of PD?

Answer 16

>90% of patients display additional non-motor symptoms, including:
Common:
	- Depression & Anxiety
	- Loss of smell
	- Sleep disorders
	- Constipation
Less common but more frequent than general population:
	- Dementia 
	- Other psychiatric complications

Question 17

What are the pathological hallmarks of PD?

Answer 17

Loss of dopaminergic neurons of the substantia nigra
Proteinopathy again!
Lewy bodies
- Intracellular protein aggregates
- Enriched in α-synuclein protein
Normal role of α-synuclein is poorly understood (involved in neurotransmitter release)
Lewy bodies not pathogenic, but ↑ α-synuclein, that causes them, is

Question 18

What are the causes of PD?

Answer 18

Familial PD
~10% of cases have a clear genetic cause
Three rough categories
1. Early/Juvenile-onset recessive mitochondrial conditions
2. Late/later-onset (usually) autosomal dominant PD
3. Mutations that cause “PD-plus” conditions- conditions that are rare and come with additional complications

Question 19

how is early-onset mitochondrial PD caused?

Answer 19

Mitochondria have a finite lifespan due to oxidative stress
Damaged mitochondria are selectively removed from the cell by “mitophagy” – autophagy of mitochondria
Loss-of-function mutations in two proteins central to activating mitophagy – PINK1 and Parkin – cause EO PD
- Mutations in at least 3 other genes linked to mitochondrial stress responses also linked to EO PD
Limitation: this PD is distinct from late-onset sporadic PD (a whole different disease?)
- Progression is different etc. so may be a whole different disease

Question 20

What causes late-onset genetic PD?

Answer 20

Some genetic causes found from kindred studies (like EO PD), but more limited, including:
- SNCA (α-synuclein) gene amplification
· Confirms that α-synuclein is pathogenic
- LRRK2 gain-of-function
- VPS35 gain-of-function
- GBA loss-of-function

Question 21

What do GBA and α-synuclein do and how are they connected?

Answer 21

GBA encodes GCase (β-glucocerebrosidase ), a lysosomal enzyme
α-synuclein is degraded in the lysosome
They are connected…
Ordinarily is the GCase enzyme is trafficked into the lysosome from the Golgi/ER and the lysosome is healthy and able to act as the final part of mitophagy where it can degrade a-synuclein
In a mutation causing less GCase activity or expression impairs the lysosome leading to a reduction in a-synuclein
So now it can accumulate
If you don’t have a GBA mutation the alpha-synuclein increase inhibits the translocation of GCase into the lysosome causing an impaired lysosome
This has been described as a pathogenic feed-forward loop

Question 22

How do PD genes play roles in lysosomes?

Answer 22

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)
Endocytic pathways are a big focus in PD research

Question 23

How is Tau linked to PD?

Answer 23

Linkage of MAPT to PD was a big surprise
Neurofibrillary tangles can be found in PD brains (even in same cells as Lewy bodies), but not to any great extent
However:
- More NFTs in brains of LRRK2 PD
- Microtubule disruption long implicated in PD

Question 24

What are the non-genetic risk factors of PD?

Answer 24

Gender (more common in men)
Red hair (~2x risk)
Head injury
Not smoking, not consuming caffeine
Herbicides, pesticides, insecticides
Exposure to metals (i.e. welder)
General anaesthesia

Question 25

What is neuroinflammation and how does it happen?

Answer 25

Neuroinflammation = activation of the immune system within the nervous system
In the brain, this principally means activation of microglia (astrocytes are also involved)
Reactive microglia:
- Is an ameboid shape
- Is more motile
- Produces cytokines
- Eventually phagocytic

Question 26

How are neuroinflammation and neurodegeneration connected?

Answer 26

Lets start with a neurotoxic insult such as injury, toxin, gene mutation etc
The damaged neuron releases factors that will activate the microglia
The microglia becomes reactive and it secretes various neurotoxic factors such as IL-1B, TNF-a and prostaglandins that will trigger more cell damage and cell death
We end up with another positive feed forward cycle

Question 27

How does ageing affect microglia?

Answer 27

Reactive microglia can be protective of neurons or damaging
Protective
- anti-inflammatory, e.g. TGFβ
- normal removal of unhealthy cells (i.e. homeostasis)
Damaging
- pro-inflammatory, e.g. IL-1, TNF-α
- response to pathogens etc (i.e. damage to neurons = ‘collateral damage’)
- Aging induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression- Neuroinflammaging

Question 28

What are the other effects in gene expression that come with ageing?

Answer 28

Shortening of telomeres in adult stem cells so cannot replace dying neurons as well
Increased reactive oxygen species so increased stress in neurons
Other changes in gene expression
- Altered Wnt signalling is a big focus in AD and PD
- Wnts are neuroprotective and neuromodulatory
- Wnt/β-catenin is decreased in adult brain
- Deregulated Wnts in developmental and geriatric neuro conditions?!