Neurodegenerative diseases

Question 1

What does neurodegenerative diseases affect? When can it occur?

Answer 1

Affects the CNS or PNS

At any stage of life

• Most common ones associated with ageing
• rarer types begin in childhood or birth
• earlier onset = greater genetic contribution
• later onset = more likely sporadic or idiopathic disease

Question 2

What similar pattern do neurodegenerative diseases follow?

Answer 2

1. Molecular impairment somewhere in the cell
2. Decreases transmission at synapse, first symptom/place impairment manifests
3. From the synapse there is “dying back” of neurites (Axons and/or dendrites) - ultimately progresses back to cell body
4. Leads to cell death

Question 3

When is onset of Alzheimers? What does it cause?

What are the symptoms?

Answer 3

Onset >65 years of age, 10% of cases are early onset, 30 years onwards.

Most common cause of dementia

Decline in memory and other cognitve functions that impair quality of life.

Sudden changes in personality, changes of mood.

Question 4

What are the pathological hallmarks of alzheimers?

Answer 4

Brain damage, brain has shrunk. The cerebral cortex, hippocampus shrink. Sulci appear deeper. Ventricles enlarge.

Proteinopathies, aggregation of proteins.

• Amyloid plaques- round bodies that sit outside the cell. Extracellular protein aggregates enriched in A beta peptides
• neurofibrillary tangles are within the cell, also called helical filaments. Intracellular protein aggregates enriched in Tau protein.

Question 5

Where is A beta peptide cleaved from?

Answer 5

A transmembrane protein, amyloid beta precursor protein (APP) by proteases.

Fragment corresponding to A beta is outside cell.

Beta-secretase and then y-secretase cleave APP, releasing A beta fragment that accumulates and forms amyloid plaque outside cell.

Question 6

What is the amyloid hypothesis?

Answer 6

Mutations to three proteins involved in AB peptide processing are known to cause rare early onset forms of Alzheimer’s

• APP gene
• PSEN1
• PSEN2

Presenilin-1 and 2 both are components of y-secretase

Since early 1990’s Amyloid hypothesis of AD which states that AB and/or amyloid plaques are the cause of AD

Question 7

What does tau displacement cause?

Answer 7

Tau normally binds microtubules in axons

Hyperphosphorylated (by kinases and serine, threonine and tyrosine) tau is displaced causing

• Tangles
• Destabilised microtubules

Question 8

What are the 3 main roles of microtubules in post-mitotic cells?

Answer 8

Structure/shape of cell, holding plasma membrane in place

Positioning of organelles

Motorways for transporting vesicular cargo e.g proteins, lipids going between organelles and across the cell

Question 9

What is the tau hypothesis?

Answer 9

In typical late onset AD (not genetic forms of AD), neurofibrillary tangles are:

• Seen before amyloid plaques
• Correlated with cell death and progression of disease e.g advanced Alzheimer’s will have lots of tau. Where cell death is and tangles are is correlated with the domains of cognition that are affected.

Suggests Tau is upstream AB peptide = Tau hypothesis

Effects of Tau causes those in AB

Question 10

What are risk factors for AD?

Answer 10

Down syndrome (APP is on chromosome 21)

High BP, cardiovascular disease, diabetes

Gender (more common in women)

Low education, education provides cognitive reserve

Head injury, trauma

Smoking and drinking

Only a small genetic risk contribution for late-onset AD (APOE gene status most significant)

Question 11

When is onset of Parkinson’s disease?

Answer 11

60-65 years of age, 10% before 45.

Lifetime risk of males 2%, females 1.3%

Question 12

What are the symptoms of Parkinson’s?

Answer 12

Movement disorder with four cardinal features

1. Resting tremor, present when person isn’t doing anything. Begins in one side of body, then goes to feet and then to the other side
2. Bradykinesia (slow movement)
3. Rigidity
4. Postural instability (fall over)

Younger patients tend to get resting tremor first, patients who develop it later in life it manifests with bradykinesia and rigidity.

Question 13

What are the non-motor symptoms of Parkinson’s?

Answer 13

>90% of patients display additional non-motor symptoms including:

Depression and anxiety

Loss of smell

Sleep disorders

Constipation

Dementia

Other psychotic complications

Question 14

What are the pathological hallmarks of Parkinson’s?

Answer 14

Loss of dopaminergic neurones of the substantia nigra – neurones that produce dopamine.

• Substantia nigra is part of basal ganglia in midbrain – means dark substance – neuromelanin is dopaminergic neurones of substantia nigra
• In Parkinson’s, there is lack of pigmentation, shows loss of dopaminergic neurones in substantia nigra

Question 15

What is the other hallmark of PD?

Answer 15

Proteinopathy.

Lewy bodies

• intracellular protein agrgegates
• enriched in a-synuclein protein
• lewy bodies not pathogenic but increase in a-synuclein is

Question 16

What three categories do genes in famiilal PD fall under?

Answer 16

Early/juvenile-onset recessive mitochondrial conditions – autosomal recessive mutations

Late/later-onset (usually) autosomal dominant PD

Mutations that cause “PD-plus” conditions - rare

Question 17

What causes early onset mitochondrial PD?

Answer 17

Mitochondria have a finite lifespan due to oxidative stress - damaged

Damaged mitochondria are selectively removed from the cell by mitophagy – autophagy of mitochondria – components can be recycle and reused

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

Question 18

What are some genetic causes of PD?

Answer 18

SNCA (a-synuclein) gene amplification – mutation, linked to genetic forms of PD

• Confirms that a-synuclein is pathogenic

LRRK2 gain-of-function mutation

VPS35 gain-of-function mutation

GBA loss-of-function mutation - a dominant loss of function, these patients are carriers of a recessive mutation. If they had both copies, they would get Gaucher disease, a type of lysosomal storage disorder.

Question 19

How is GBA functionally linked to a-synuclein?

Answer 19

GBA encodes GCase (B-glucocerebrosidase), a lysosomal enzyme

A-synuclein is degraded in the lysosome

They are connected

Question 20

What does a mutation in GBA or GCase cause?

Answer 20

Normally GCase is trafficked into lysosome from other organelles, acts as final part of autophagy and mitophagy, degrades a-synunclein so there is no accumulation, no lewy bodies, no PD.

With mutation there is less active GCase in lysosome, lysosome is impaired. Can’t function in autophagy, a-synuclein accumulates.

Question 21

What does excess a-synuclein due to other mutations/ sporadic PD cause?

Answer 21

Excess inhibits translocation of GCase into lysosome

Impaired lysosome unavle to act efficiently in autophagy, more accumulation of a-synuclein

Pathogenic feedforward loop:

• Increase a-synuclein
• decreases GCase translocation into lysosome
• decreases lysosomal function carrying out autophagy
• leading to more a-synuclein

both increased a-synunclein and decreased lysosomal function cause cell death

Question 22

What are other risk factors for PD?

Answer 22

Gender (more common in men)

Red hair (2x risk)

Head injury

Not smoking, not consuming caffeine

Herbicides, pesticides, insecticides typically those that impair mitochondria

Exposure to metals e.g welder, likely to inhale metal

General anaesthesia

Question 23

What is neuroinflammation? What are reactive microglia?

Answer 23

Neuroinflammation = activation of the immune system within the nervous system

In the brain this principally means the activation of microglia (Astrocytes also involved).

Reactive microglia

• Amoeboid shape
• More motile in that shape
• Production of cytokines
• Eventually phagocytic and able to engulf bits of cellular debris and pathogens

Question 24

How does microglia cause neuroinflammation?

Answer 24

Neuronal death causes neurone to release factors e.g a-synuclein, which activate microglia.

Microglia secrete neurotoxic factors e.g IL-1B, TNF-a, prostaglandins

Triggers more cell damage and death

Positive feed forward cycle, neuroinflammaton amplifies effects of neurodegeneration

Question 25

How are microglial protective of neurons?

Answer 25

Release anti -inflammatory cytokines e.g TGFB

Homeostatic role, normal removal of unhealthy cells without causing further injury to the host

Question 26

How are microglia damaging of neurones?

What does ageing induce?

Answer 26

Pro-inflammatory cytokines e.g IL-1, TNF-a

Response to pathogens etc ie. Damage to neurons = collateral damage , price worth paying to avoid something else such as dying from a pathogen infection

Ageing causes shift towards production of damaging reacting microglia due to changes in microglia gene expression - neuroinflamation

Question 27

What are the other effects of ageing?

Answer 27

Shortening of telomeres in adult stem cells, not able to replace dying neurones as well

Increase in reactive oxygen species with ageing, increasing stress on neurones

Other changes in gene expression:

• Altered Wnt signalling is a big focus in AD and PD
• Wnt ligands are neuroprotective and neuromodulatory, stop neurones from dying – play role in cognition
• Wnt/B-catenin is decreased in adult brain
• Deregulated Wnts in developmental and geriatric neuro conditions?!