Loss of Proteostasis & Neurodegeneration Flashcards
What is a key feature of neurodegenerative diseases?
Protein aggregation
What is proteostasis?
Proteostasis is the process by which organisms maintain a healthy balance of proteins.
How do young adult worms maintain a balanced proteome?
By effectively clearing misfolded proteins.
What contributes to proteome imbalance?
- 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
What is associated with proteome imbalance?
Ageing
Alzheimer’s Disease is characterised by which two distinctive neuropathological lesions?
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)
What is the energy usage of the human brain?
10-15 Watts; >1016 complex operations per second (10 petaflops)
How many neurons and synapses are there in the brain?
There are around 100 billion neurons and 100 trillion synapses.
What are neurons responsible for?
Neurons are responsible for storage and retrieval of biological data.
Do neurons proliferate?
Neurons are terminally differentiated and non-proliferative.
Cells proliferate at different rates depending on their function. Give an example of a mitotic cell, its lifespan and cell cycle length.
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.
Cells proliferate at different rates depending on their function. Give an example of a quiescent (dormant) cell, its lifespan and cell cycle length.
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.
Cells proliferate at different rates depending on their function. Give an example of a fixed post mitotic cell, its lifespan and cell cycle length.
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.
Cells age at different rates. Provide a reason why.
Telomere lengths vary.
How old will the neurons of an 100 year old person be?
The neurons will range from around 80-100 years old and will have withstood a lifetime of biological insults.
True or false: Neurons are replaced.
False - neurons are not replaced and instead must repair themselves.
Misfolded proteins build up in neurons as a result of which characteristic?
The inability of neurons to divide
As neurons cannot be replaced, they must be repaired. How do they do this?
Neurons continuously adjust, or remodel, their synaptic connections depending on how much stimulation they receive from other neurons.
Describe familial Alzheimer’s Disease.
- Early onset (<65 years old)
- Unimodal progeroid disease
- Autosomal dominant
- Identified using genetic linkage studies
- First type to be identified
Describe sporadic Alzheimer’s Disease.
- Late onset (>65 years old)
- Found in the general population
- Caused by SNPs with small effect sizes
- Identified using GWAS
Which genotype is the biggest genetic risk factor for late onset Alzheimer’s Disease?
ApoE4
Which three genes are linked to familial Alzheimer’s Disease?
APP, PSEN1 and PSEN2
The Aβ peptide is a small fragment of which protein?
Amyloid-β Precursor Protein (APP)
What type of protein is APP?
APP is a transmembrane protein with a structure similar to some cell surface receptors involved in a variety of cell signalling pathways.
What is the function of APP?
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
What is the amyloid cascade hypothesis?
The amyloid cascade hypothesis is a theory that Alzheimer’s Disease is caused by a build up of Aβ peptides in the brain.
What is a secretase?
A membrane-bound enzyme which cuts off pieces of proteins which are embedded in the cell membrane.
What is the name of the system which the secretases constitute?
Regulated Intramembrane Proteolysis
How is the Aβ peptide produced from APP?
Aβ is produced by sequential cleavage of APP by beta-secretase and gamma-secretase
How long are Aβ peptides?
Varying length from ~36-43 amino acids.
Which pathway leads to ogliomerisation and aggregation, as well as degradation, of Aβ peptides?
Amyloidogenic pathway
What does the non-amyloidogenic APP pathway result in?
p3
Which four proteins make up gamma-secretase?
PSEN1, nicastrin, APH-1 and PEN-2.
What does gamma-secretase do?
Cleaves substrates within the membrane such as APP and transmembrane receptors
How does gamma-secretase differ from other secretases?
Most secretases cut at very specific sites in target proteins however gamma-secretase cleavage generates different sizes of Aβ peptides.
What does Aβ38 lead to?
No aggregation
What does Aβ40-42 lead to?
Some aggregation
What does high levels of Aβ42 lead to?
High levels of aggregation leading to amyloid plaques which causes increased cell death which can lead to dementia.
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?
Many of these mutations will increase amyloidogenic processing of APP leading to increased Aβ41-42 production therefore increased neurotoxicity and Alzheimer’s Disease.
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?
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.
On which chromosome is APP? What effect does this have?
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.
What are the two major pathological hallmarks of Alzheimer’s Disease?
Extracellular amyloid plaques (Aβ) and intracellular neurofibrillary tangles (Tau).
True or false: Mutations in the tau gene (MAPT) are linked to familial Alzheimer’s Disease?
False, mutations in MAPT are linked to other forms of dementia, such as frontotemporal dementia, but are not linked to familial Alzheimer’s disease.
Describe the microtubule associated protein Tau (MAPT).
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.
What do microtubule dynamics play an essential role in?
Active transport of axonal proteins, vesicles and organelles throughout the axon.
What effect does Tau have on microtubules?
Tau stabilises microtubules
In Alzheimer’s Disease, what happens to microtubules?
They dissociate, releasing Tau which becomes aggregated in neurofibrillary tangles.
Specific mutations in PSEN and APP cause all carriers to get familial Alzheimer’s Disease as they increase the amount of…
Aβ42 produced
By which mechanism do rare mutations in APP protect against Alzheimer’s Disease?
They decrease beta-secretase cleavage therefore increasing alpha-secretase cleavage, overall reducing Aβ.
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?
Some alleles of APP prevent Alzheimer’s disease
Current efforts in finding new therapeutic strategies for Alzheimer’s Disease focus on what?
Clearance mechanisms of toxic Aβ ogliomers.
