Loss of Proteostasis & Neurodegeneration

Question 1

What is a key feature of neurodegenerative diseases?

Answer 1

Protein aggregation

Question 2

What is proteostasis?

Answer 2

Proteostasis is the process by which organisms maintain a healthy balance of proteins.

Question 3

How do young adult worms maintain a balanced proteome?

Answer 3

By effectively clearing misfolded proteins.

Question 4

What contributes to proteome imbalance?

Answer 4

• Inefficient clearance of misfolded proteins and misregulated transcription
• Loss of chaperones such as sHSP (small heat shock protein)
• Increase in the number of toxic misfolded protein ogliomers
• Insoluble inclusions - large aggregates of misfolded ogliomers

Question 5

What is associated with proteome imbalance?

Answer 5

Ageing

Question 6

Alzheimer’s Disease is characterised by which two distinctive neuropathological lesions?

Answer 6

1) Extracellular deposits called amyloid plaques - composed of beta-amyloid peptide aggregates
2) Intracellular accumulation of neurofibrillary tangles made of hyperphosphorylated Tau proteins (these tangles are also known as Tau fibrils)

Question 7

What is the energy usage of the human brain?

Answer 7

10-15 Watts; >10¹⁶ complex operations per second (10 petaflops)

Question 8

How many neurons and synapses are there in the brain?

Answer 8

There are around 100 billion neurons and 100 trillion synapses.

Question 9

What are neurons responsible for?

Answer 9

Neurons are responsible for storage and retrieval of biological data.

Question 10

Do neurons proliferate?

Answer 10

Neurons are terminally differentiated and non-proliferative.

Question 11

Cells proliferate at different rates depending on their function. Give an example of a mitotic cell, its lifespan and cell cycle length.

Answer 11

Mitotic cells are continuously dividing. An example is skin cells which have a lifespan of around 3 weeks and a cell cycle length of 12-24 hours.

Question 12

Cells proliferate at different rates depending on their function. Give an example of a quiescent (dormant) cell, its lifespan and cell cycle length.

Answer 12

Quiescent cells undergo low or no division but can be stimulated to divide. An example is the liver cells which have a lifespan of around 200-300 days and a cell cycle length of 1-2 years.

Question 13

Cells proliferate at different rates depending on their function. Give an example of a fixed post mitotic cell, its lifespan and cell cycle length.

Answer 13

Fixed post mitotic cells do not undergo division, even when stimulated. An example is neurons which have a lifespan the same as that of the organism they are present in and do not undergo cycles.

Question 14

Cells age at different rates. Provide a reason why.

Answer 14

Telomere lengths vary.

Question 15

How old will the neurons of an 100 year old person be?

Answer 15

The neurons will range from around 80-100 years old and will have withstood a lifetime of biological insults.

Question 16

True or false: Neurons are replaced.

Answer 16

False - neurons are not replaced and instead must repair themselves.

Question 17

Misfolded proteins build up in neurons as a result of which characteristic?

Answer 17

The inability of neurons to divide

Question 18

As neurons cannot be replaced, they must be repaired. How do they do this?

Answer 18

Neurons continuously adjust, or remodel, their synaptic connections depending on how much stimulation they receive from other neurons.

Question 19

Describe familial Alzheimer’s Disease.

Answer 19

• Early onset (<65 years old)
• Unimodal progeroid disease
• Autosomal dominant
• Identified using genetic linkage studies
• First type to be identified

Question 20

Describe sporadic Alzheimer’s Disease.

Answer 20

• Late onset (>65 years old)
• Found in the general population
• Caused by SNPs with small effect sizes
• Identified using GWAS

Question 21

Which genotype is the biggest genetic risk factor for late onset Alzheimer’s Disease?

Answer 21

ApoE4

Question 22

Which three genes are linked to familial Alzheimer’s Disease?

Answer 22

APP, PSEN1 and PSEN2

Question 23

The Aβ peptide is a small fragment of which protein?

Answer 23

Amyloid-β Precursor Protein (APP)

Question 24

What type of protein is APP?

Answer 24

APP is a transmembrane protein with a structure similar to some cell surface receptors involved in a variety of cell signalling pathways.

Question 25

What is the function of APP?

Answer 25

The function of APP is not completely clear however it is known to be implicated in:
* signalling of Neuronal Stem Cell development
* intracellular signalling systems which promote growth of axonal and dendritic processes
* synaptic maintenance and remodelling synaptic plasticity
* regulating lipid homeostasis

Question 26

What is the amyloid cascade hypothesis?

Answer 26

The amyloid cascade hypothesis is a theory that Alzheimer’s Disease is caused by a build up of Aβ peptides in the brain.

Question 27

What is a secretase?

Answer 27

A membrane-bound enzyme which cuts off pieces of proteins which are embedded in the cell membrane.

Question 28

What is the name of the system which the secretases constitute?

Answer 28

Regulated Intramembrane Proteolysis

Question 29

How is the Aβ peptide produced from APP?

Answer 29

Aβ is produced by sequential cleavage of APP by beta-secretase and gamma-secretase

Question 30

How long are Aβ peptides?

Answer 30

Varying length from ~36-43 amino acids.

Question 31

Which pathway leads to ogliomerisation and aggregation, as well as degradation, of Aβ peptides?

Answer 31

Amyloidogenic pathway

Question 32

What does the non-amyloidogenic APP pathway result in?

Answer 32

p3

Question 33

Which four proteins make up gamma-secretase?

Answer 33

PSEN1, nicastrin, APH-1 and PEN-2.

Question 34

What does gamma-secretase do?

Answer 34

Cleaves substrates within the membrane such as APP and transmembrane receptors

Question 35

How does gamma-secretase differ from other secretases?

Answer 35

Most secretases cut at very specific sites in target proteins however gamma-secretase cleavage generates different sizes of Aβ peptides.

Question 36

What does Aβ38 lead to?

Answer 36

No aggregation

Question 37

What does Aβ40-42 lead to?

Answer 37

Some aggregation

Question 38

What does high levels of Aβ42 lead to?

Answer 38

High levels of aggregation leading to amyloid plaques which causes increased cell death which can lead to dementia.

Question 39

What is the effect of the V717I (“London”) mutation of APP which causes a change in valine to isoleucine close to the gamma-secretase cleavage site?

Answer 39

Many of these mutations will increase amyloidogenic processing of APP leading to increased Aβ41-42 production therefore increased neurotoxicity and Alzheimer’s Disease.

Question 40

What is the effect of the A673T (“Icelandic”) mutation of APP which causes a change from alanine to threonine close to the beta-secretase cleavage site?

Answer 40

Reduces beta-secretase cleavage therefore increasing alpha-secretase cleavage. This results in a reduction in amyloidogenic processing of APP, leading to less Aβ41-42 production and neuroprotection.

Question 41

On which chromosome is APP? What effect does this have?

Answer 41

APP is on chromosome 21 which is also where Down’s Syndrome is found. Those with Down’s Syndrome will therefore have three copies of APP hence more Aβ.

By age 40 almost all people with Down’s syndrome have amyloid plaque deposits and Tau tangles in the brain. Over 50% of those with Down’s Syndrome develop dementia due to Alzheimer’s disease.

Question 42

What are the two major pathological hallmarks of Alzheimer’s Disease?

Answer 42

Extracellular amyloid plaques (Aβ) and intracellular neurofibrillary tangles (Tau).

Question 43

True or false: Mutations in the tau gene (MAPT) are linked to familial Alzheimer’s Disease?

Answer 43

False, mutations in MAPT are linked to other forms of dementia, such as frontotemporal dementia, but are not linked to familial Alzheimer’s disease.

Question 44

Describe the microtubule associated protein Tau (MAPT).

Answer 44

It has a nucleus in the cell body, a very long axon and proteins and organelles which are transported from the cell body to the synapse.

Question 45

What do microtubule dynamics play an essential role in?

Answer 45

Active transport of axonal proteins, vesicles and organelles throughout the axon.

Question 46

What effect does Tau have on microtubules?

Answer 46

Tau stabilises microtubules

Question 47

In Alzheimer’s Disease, what happens to microtubules?

Answer 47

They dissociate, releasing Tau which becomes aggregated in neurofibrillary tangles.

Question 48

Specific mutations in PSEN and APP cause all carriers to get familial Alzheimer’s Disease as they increase the amount of…

Answer 48

Aβ42 produced

Question 49

By which mechanism do rare mutations in APP protect against Alzheimer’s Disease?

Answer 49

They decrease beta-secretase cleavage therefore increasing alpha-secretase cleavage, overall reducing Aβ.

Question 50

The existence of both causative and protective APP alleles strongly suggests Aβ is the primary cause of Alzheimer’s Disease. Why can’t Tau cause Alzheimer’s on its own?

Answer 50

Some alleles of APP prevent Alzheimer’s disease

Question 51

Current efforts in finding new therapeutic strategies for Alzheimer’s Disease focus on what?

Answer 51

Clearance mechanisms of toxic Aβ ogliomers.