Post Translational Processing

Question 1

What is a protein aggregation disorder?

What are some examples?

Answer 1

A disorder in which misfolded proteins clump together and are deposited, often due to post-translational processing.
Eg. Alzhemiers, parkinsons, dementia with lewy bodies, frontotemporal dementia, amyloidosis, prion disease

Question 2

What is the pathology of Alzheimers?

Answer 2

Amyloid beta is cleaved from the amyloid precursor protein on chromosome 21.
This substance accumulates in the brain, forming senile plaques which prevent communication between neuronal populations.

Question 3

If you measured CSF in an Alzheimers patient, what key finding would be low?

Answer 3

Low amyloid beta as it is drawn into the brain to compensate for the loss

Question 4

How can therapy target post translational processing in Alzheimers?

Answer 4

• Inhibition of enzymes (beta/gamma secretes) that cleave the amyloid precursor protein
• Immunisation with Amyloid beta peptide seems to reduce senile plaques

Question 5

What is the pathology of frontotemporal dementia?

Answer 5

During PTM, tau gets hyperphosphorylated and detaches from the microtubule, meaning it can aggregate more freely.
This build up leads to NEUROFIBRILLARY TANGLES of tau

NB this also occurs in AD!

Question 6

If you measured CSF-pTAU in an FTLD patient, what would it be ?

Answer 6

High - protein leaking out of dying cells

Question 7

How can therapy target PTM in FTLD?

Answer 7

Tau aggregation inhibitors

Question 8

What is the pathology of Parkinson’s Disease and Dementia with lewy bodies?

Answer 8

Changes in phosphorylation and solubility of a-synuclein make it more likely to aggregate, to form lewy bodies.

This can be due to genetics!

This is paired with a loss of dopaminergic neurones in the substantia nigra

Question 9

What CSF biomarkers exist for PD?

Answer 9

Oligomeric and phosphorylated tau - these are slightly increased

Question 10

How do Metformin, Dasatinib and vaccination have a role in PD therapy?

Answer 10

• Metformin acts on tau phosphorylation via PP2A signalling
• Dasatinib inibits cABL tyrosine kinase, which is involved in phosphorylation
• Vaccination with a-synuclein can prevent protein folding

Question 11

What is a lysosomal storage disorder?

Answer 11

A group of inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of digestive enzyme.

Question 12

Describe the genetics and pathology behind LSDs?

Answer 12

A recessive disorder involing a single point mutation that leads to:

1. Loss of function mutation of enzyme, leading to abnormal protein folding in PTM
2. Progressive accumulation of abnormal metabolite within lysosomes
3. Progressive dysfunction of phagocyte/macropahage system in the reticuloendothelium
4. Abnormal build up of toxic material and organ dysfunction.

Question 13

What are the two main categories of lysosomal storage disorders, and examples in each of these?

Answer 13

Sphingolipidases - Gauchers, Tay-Sachs, Neimann-Pick

Mucopolysaccharidoses - Hunter Hurler Sche syndrome, Hurlers syndrome

Question 14

What are the features of Gauchers Disease, and what types are there?

Answer 14

• Thrombocytopenia
• Neurological deficit
• Pulmonary involvement
• Hepatosplenomegaly

Fatigue, anaemia, yellow sclera

Type 1 - slowly progressive (common)
Type 2 - rapid with neurological changes
Type 3 - Intermediaet (rare, teens)

Question 15

What is the pathology of Gauchers?

Answer 15

Sphingolipidose lysosomal storage disorder involving a Ig22 recessive mutation of glucocerebrosidase, causing accumulation of glucocerbroside in cells and certain organs

Question 16

How can Gauchers be treated?

Answer 16

1. Enzyme replacement
2. Symptomatic
3. Enzyme refolding using pharmacological chaperones. These help stabilise the protein in the ER

Question 17

What is Tay Sachs disease?

Answer 17

Sphingolipidose lysosome storage disorder causing destruction of CNS nerve cells causing seizures, hearing loss and inability to move

Question 18

What are the features of Hunters syndrome?

Answer 18

Skeletal deformities
Developmental delay
Hepatosplenomegaly
Cardiac and lung abnormalities

Question 19

What is the pathophysiology of Hunters syndrome?

Answer 19

Mucopolysaccharide lysosomal storage disorder, involving Xq28 mutation, causing iduronate 2-sulfatase deficiency, and accumulation of HEPARIN SULPHATE

Question 20

How can Hunters syndrome be treated?

Answer 20

1. Bone marrow transplantation

2. Intrathecal idusulfase

Question 21

What is Hurler Schei syndrome?

Answer 21

A mucopolysaccharide lysosomal storage disorder, involving a mutation causing alpha L iduronase deficiency.

Features are skeletal deformities, developmental delay, hepatosplenomegaly, CORNEAL CLOUDING

Question 22

How is Hurler Schei syndrome treated

Answer 22

1. Bone marrow transplantation

2. Intrathecal iaronidase