Pathology of Neurodegenerative diseases - Parks

Question 1

What do Parkinson’s, Alzheimer’s, Huntington’s and ALS have in common?

Answer 1

They all show a progressive loss of neurons in specific areas and they all involve protein inclusions.

Question 2

What two proteins form inclusions in Alzheimer’s disease?

Answer 2

1. ABeta amyloid protein

2. Tau protien

Question 3

What protein forms inclusions in Parkinson’s disease?

Answer 3

Alpha-synuclein protein.

Question 4

What proteins form inclusions in ALS?

Answer 4

TDP-43 and SOD-1.

Question 5

What protein forms inclusions in Huntington’s disease?

Answer 5

Huntington’s protein.

Question 6

What happens to proteins that are misfolded, damaged or old?

Answer 6

They are broken down.

Question 7

What are the two processes by which proteins may be broken down?

Answer 7

1. the protein is ubiquinated and sent to a proteosome

2. proteins aggregate, get surrounded by a double membrane and undergo autophagy in a lysosome

Question 8

If ‘bad’ proteins are normally broken down, how do inclusion bodies form?

Answer 8

These proteins gain resistance to being broken down by proteosomes or via autophagy and so they can aggregate and form inclusion bodies.

Question 9

Aggregated proteins do what to neurons?

Answer 9

Cause neuron death.

Question 10

How do protein aggregates damage neurons and lead to neuronal death?

Answer 10

1. Often they elicit a STRESS reaction from the cell.
2. Often directly TOXIC to the neurons
3. Some aggregates are capable of behaving like prions. Aggregates derived from one neuron taken up by another neuron giving rise to more aggregates.

Question 11

Describe a pathway that leads to neurodegeneration.

Answer 11

1. native protein monomers are misfolded
2. They form beta sheet oligomers and amyloid fibrillar aggregates
3. cells get stressed and die or the mutant protein is directly toxic

Question 12

What is amyloid?

Answer 12

insoluble fibrous protein aggregates sharing specific structural traits. They arise from at least 18 inappropriately folded versions of proteins and polypeptides present naturally in the body.[1] These misfolded structures alter their proper configuration such that they erroneously interact with one another or other cell components forming insoluble fibrils. They have been associated with the pathology of more than 20 serious human diseases in that abnormal accumulation of amyloid fibrils in organs may lead to amyloidosis, and may play a role in various neurodegenerative disorders

Question 13

Describe the basic pathology of Alzheimer’s?

Answer 13

In the cortex:

1. extracellular amyloid plaques are deposited
2. neurofibrillary tangles are formed inside cortical neurons
3. the abnormal proteins cause loss of neurons and gliosis leading to atrophy of brain tissue
4. damage usually starts around the hippocampus

Question 14

In Alzheimer’s amyloid plaques are formed from what?

Answer 14

A-Beta amyloid protein.

Question 15

In Alzheimer’s neurofibrillary tangles are made from what?

Answer 15

Tau protein.

Question 16

A-Beta amyoid protein normally resides where?

Answer 16

It is a membrane protein - called amyloid precursor protein when not a mutant. It is normally cleaved by secretases into a harmless soluble peptide.

Question 17

What happens to make A-Beta amyloid instead of soluble amyloid precursor protein?

Answer 17

If amyloid precursor protein is cleaved by B-amyloid converting enzyme or BACE and gamma secretes then A-Beta peptides are released. They form pathogenic aggregates characteristic of plaques and leading to tangles in Alzheimer’s.

Question 18

How does A-Beta amyloid function in Tau aggregation and formation of neurofibrillary tangles?

Answer 18

It leads to the phosphorylation (by turning on a kinase that phosphorylates Tau) of Tau proteins which causes them to aggregate.

Question 19

What is the normal function of Tau protein and what makes it form aggregates?

Answer 19

Tau normally functions to stabilize microtubules. If it is phosphorylated then it comes off of microtubules. The microtubules disassemble and Tau forms paired helical structures that aggregate to form neurofibrillary tangles.

Question 20

Astrazeneca is a what?

Answer 20

An Alzheimer’s therapy that works as a BACE inhibitor.

Question 21

What is the amyloid cascade hypothesis?

Answer 21

The cascade leads to Alzheimer’s:

1. increased production/reduced degradation of A-Beta amyloid protein
2. plaque formation
3. hyperphosphorylation of Tau
4. neurofibrillary tangle formation
5. synaptic dysfunction and neuron loss
6. memory loss/cognitive deficits
7. psychobehavioral impairment
   8 death

Question 22

How does Alzheimer’s lead to synaptic dysfunction?

Answer 22

It disrupts the normal function of microtubules that are critical for taking things to and from the synapse.

Question 23

What is one way to look for the plaques in Alzheimer’s?

Answer 23

A tracer called Amyvid - a molecule that binds to A-Beta amyloid in the brain - is used to visualize plaques during a PET scan.

Question 24

Is the presence alone of plaques in the brain indicative of Alzheimer’s?

Answer 24

No. Plaques and NF tangles are also seen with normal aging and no cognitive decline.

Question 25

What are the expected CSF findings in the case of Alzheimer’s?

Answer 25

1. low Beta amyloid
2. high total Tau
3. elevated phosphorylated TAu
4. this is called the AD (Alzheimer’s dementia) signature
5. These biomarkers have a low specificity for Alzheimer’s because it is also expected in the aged

Question 26

What part of the brain is affected in Parkinson’s disease?

Answer 26

The basal ganglia - specifically the substantial nigra.

Question 27

What is the function of the basal ganglia?

Answer 27

Modulation and control of motor function.

Question 28

What type of neurons are in the substantial nigra?

Answer 28

Dopaminergic neurons projecting to the striatum. These are damaged in Parkinson’s.

Question 29

What is one treatment for Parkinson’s?

Answer 29

L-Dopa therapy.

Question 30

Grossly, what will happen to the substantial nigra in Parkinson’s?

Answer 30

It will become depigmented.

Question 31

What makes up the striatum?

Answer 31

1. caudate nucleus

2. putamen

Question 32

What are some of the symptoms and signs of Parkinson’s?

Answer 32

1. tremor
2. mask-like facies
3. arms flexed at elbows and wrists
4. short, shuffling steps
5. stooped posture
6. rigidity
7. hips and knees slightly flexed

Question 33

In Parkinson’s what is causing death of dopaminergic neurons?

Answer 33

Inclusion bodies formed from alphasynuclein protein.

Question 34

Lewy bodies can cause what in Parkinson’s?

Answer 34

They can cause Lewy body dementia. Alphasynuclein protein aggregates can act like prions and form lewy bodies which are inclusion bodies.

Question 35

What is ALS?

Answer 35

Amytrophic lateral sclerosis. It is a motor neuron disease.

Question 36

Does ALS involve upper or lower motor neurons?

Answer 36

Both!

Question 37

ALS is characterized by what?

Answer 37

1. Muscle atrophy, weakness and fasciculation.
2. Wollerian degeneration of axons following neuron death that leads to gliosis of the lateral columns of the spinal cord
3. degeneration of motor roots in the anterior horns

Question 38

What is the mutant protein involved in ALS?

Answer 38

SOD or superoxide dismutase. This enzyme normally dismantles superoxide and protects the cell.

Question 39

In ALS, mutant SOD aggregates but also does what?

Answer 39

Leads to too much release/not enough reuptake of glutamate. This leads to cytotoxicity and neuronal death.

Question 40

What is Riluzole and how is used to treat ALS?

Answer 40

This is a drug that inhibits glutamate release and blocks post-synaptic actions of NMDA receptors so it can help the cytotoxicity caused by ALS.

Question 41

Huntington’s disease is a hyperkinetic disease that primarily affects what area of the brain?

Answer 41

The Striatum, there will be atrophy of the caudate and putamen and increased size of the lateral ventricles.

Question 42

Huntington’s is considered to be what?

Answer 42

A trinucleotide repeat disorder - because it involves a CAG (glutamine) repeat expansion.

Question 43

What is the protein involved in Huntington’s?

Answer 43

The Huntington protein. The mutant protein (lots of CAG repeats) aggregates, is ubiquinated and causes inclusion in neuronal nuclei.

Question 44

Is Huntington’s hereditary?

Answer 44

Yes.

Question 45

In Huntington’s disease status depends on what?

Answer 45

The number of CAG repeats present.Increased CAG repeats results in earlier age of onset and severity.

1. Less than 26 - not affected
2. 27-35 repeats - not affected but elevated risk to offspring
3. 36-39 repeats - may or may not be affected but 50% risk for offspring
4. 40+ repeats - will be affected and 50% risk to offspring