Neuro diseases

Question 1

Define Neurodegeneration and Neurodegenerative disease

Answer 1

• Neurodegeneration = neuro (relating to neurons) + degeneration (progressive loss)
• Neurodegenerative disease = any disease caused by neurodegeneration

Question 2

What do neuro diseases affect?

When do they begin?

Answer 2

• 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 3

Have a look at some examples

Answer 3

On table

Question 4

Are Neurodegenerative diseases heterogenous and why?

Answer 4

• Neurodegenerative diseases are highly heterogeneous (varied in presentation), the reasons for this are:
o 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)
o Some diseases are inherently pleiotropic

Symptoms manifest differently in different people
(e.g. Parkinson’s disease symptoms unique to individual)

Question 5

What are the patterns of these diseases?

Answer 5

1. Molecular impairment somewhere in the cell
2. Decreased transmission at synapse
3. “Dying back” of neurites (axons and/or dendrites)
4. Cell death

Question 6

What is the distance between axon terminal and nucleus

Answer 6

a neuron’s “Achilles heel”

Question 7

What are the common features of these diseases?

Answer 7

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

Question 8

What are the clinical and research problems?

Answer 8

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

Question 9

What is dementia?

Answer 9

• A decline in memory and other cognitive functions that impair quality of life
• Impairments in dementia are distinct from “normal” cognitive lapses, e.g.

Normal ageing = gradual decline in normal cognition, gradual changes in personality

Question 10

What are the PATHOLOGICAL HALLMARKS of Alzheimers?

Answer 10

On images

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 11

What causes alzheimers disease?

Answer 11

Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases

Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s
• APP
• PSEN1 - Presenilin-1 and Presenilin-2; both a components of γ-secretase
• PSEN2 - Presenilin-1 and Presenilin-2; both a components of γ-secretase

Question 12

What is tau and how does it cause alzheimers?

Answer 12

• Tau normally binds microtubules in axons
• Hyperphosphorylated tau is displaced causing:

Tangles
Destabilised microtubules

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 13

What are the 3 roles of microtubules in neurites?

Answer 13

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

Question 14

TAU OR AMYLOID?

Answer 14

• Still really controversial!
• Probably more evidence for amyloid, but…
o Therapies based on inhibiting Aβ aggregation so far haven’t worked
• Tangles and plaques may be red herrings
o Are they pathogenic or by-standers? Or even protective?
o Oligomeric forms of Aβ and tau are more likely to be pathogenic
• Could both be downstream of other factors?

Question 15

What are the other risk factors of AD?

Answer 15

• 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 16

What are the motor and non-motor symptoms of parkinsons disease?

Answer 16

A movement disorder, with four ‘cardinal’ features

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

NON-MOTOR SYMPTOMS
•	>90% of patients display additional non-motor symptoms, including:
o	Depression & Anxiety
o	Loss of smell
o	Sleep disorders
o	Constipation
o	Dementia 
o	Other psychiatric complications

Question 17

What are the pathological hallmarks of PD?

Answer 17

On images

PATHOLOGICAL HALLMARKS 2
Proteinopathy again!
• Lewy bodies
o Intracellular protein aggregates
o Enriched in α-synuclein protein
• Normal role of α-synuclein is poorly understood (involved in neurotransmitter release)
• Lewy bodies not pathogenic, but ↑ α-synuclein is

Question 18

Can PD be inherited?

Answer 18

• 10% of cases have a clear genetic cause
• Three rough categories
a. Early/Juvenile-onset recessive mitochondrial conditions
b. Late/later-onset (usually) autosomal dominant PD
c. Mutations that cause “PD-plus” conditions

Question 19

What is early onset mitochondrial PD?

Answer 19

o Mitochondria have a finite lifespan due to oxidative stress
o Damaged mitochondria are selectively removed from the cell by “mitophagy” – autophagy of mitochondria
o 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
o Limitation: this PD is distinct from late-onset sporadic PD
(a whole different disease?)

Question 20

What is late onset PD?

Answer 20

o 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 are GBA & α-SYNUCLEIN?

Answer 21

• GBA encodes GCase (β-glucocerebrosidase ),
a lysosomal enzyme
• α-synuclein is degraded in the lysosome
• They are connected…

Question 22

How is PD and lysosomes related?

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

What have GWAS revealed?

Answer 23

• Risk genes
• Has shown many “cause genes” also influence risk
• Also found many new PD genes
• Now believed as much as 30% of PD risk is genetic

Question 24

What are other 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?

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)

Question 26

How can neuroinflammation lead to neurodegeneration?

Answer 26

On image

Question 27

What are the protective and damaging roles of microglia?

Answer 27

• Reactive microglia can be protective of neurons or damaging
• Protective
o anti-inflammatory, e.g. TGFβ
o normal removal of unhealthy cells (i.e. homeostasis)
• Damaging
o pro-inflammatory, e.g. IL-1, TNF-α
o response to pathogens etc
(i.e. damage to neurons = ‘collateral damage’)

Question 28

How is aging related to microglia?

Answer 28

Aging induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression - NEUROINFLAMMAGING

Question 29

How is PD related to the gut and brain?

Answer 29

• Lewy body pathology in gut often precedes pathology in brain
• Evidence that gut inflammation is sufficient to cause gut Lewy bodies
• Spread to brain via vagus nerve?
• Role for microbiota?

Question 30

What are the other effects of aging?

Answer 30

• Shortening of telomeres in adult stem cells
• Increased reactive oxygen species
• 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?!