Protein Aggregation Diseases

Lecture 4 - Biochemistry

Protein Aggregation Disease (8)

• Alzheimer’s

• Parkinson’s

• Sickle Cell Anaemia

• Creutzfeldt-Jakob Disease (CJD)

• Prion Disease

• Huntington Disease

• Amyotrophic Lateral Sclerosis (ALS)

• Cataract

Types of protein aggregates

1) Non-amyloid: do not contain amyloid-like cross β-structure

2) Amyloid: contain cross β-structure

Non-amyloid aggregate example

Sickle cell anaemia

Amyloid aggregate examples

Alzheimer’s, Parkinson’s, Cataract etc.

Sickle Cell Anaemia

• patients RBC lifespan is 10-20 days

• caused by a single nucleotide mutation in the oxygen transporter of hemoglobin (Hb) —> GAG to GTG replaces Glu by Val at amino acid position 6 in the β -chain of Hb.

• occurs on HBB gene in chromosome 11

• mutation from Glu —> Val at 6th amino acid in the Beta-chain, which is a charged residue to hydrophobic residue mutation.

• Hb S (sickle Hb) sticks to one aother forming long rod-like fibers, twined as a helical bundle, that distorts RBC into sickle shape.

• clogs blood veins

Hb A vs Hb S structure

Aggregates are of alpha-helical structure

The content of alpha-helical structure is similar b/w Hb S and Hb A

The interface between four polypeptide chains is more open.

Alzheimer’s Disease Overview

AD increases exponentially with age

• 5th leading cause of death

• survival is typically 4-6 years

• Can be as young as 40 years

• more common in women

Risk Factors for AD

Alterations on chromosome 1, 14, or 21

Down Syndrome and AD

people with tisomy 21, have an extra gene copy, almost universally exhibit AD by age 40 years of age.

Pathophysiology of Alzheimers

loss of neurons and synapses in the cerebral cortex and certain subcortical regions due to:

• Protein misfolding

  • Amyloid plaques

  • Neurofibrillary Tangles:

Amyloid Plaques

deposits of beta-amyloid protein generated from Alzheimer amyloid precursor protein (APP) which accumulates in spaces between nerve cells. Interferes with neuron communication with one another resulting in abnormal brain function and apoptosis.

• APP is cleaved by β-secretase and γ-secretase to form neurotoxic AB42 fragment

• AB fragment has no structure

Neurofibrillary Tangles

accumulate inside of nerve cells. They are deposits of tau proteins that are involved in microtubule formation.

• 3-4 fold higher in AD than in normal human brain

• imbalance of protein kinase and phosphatase contributes to abnormal phosphorylation of tau

• Resulting in destabilization of microtubules and self-aggregation of Tau into NFTs (neurofibrillary tangles)

How amyloid aggregates cause toxicity?

Cell machinery that might be affected by misfolded, mutant SOD1 (or any other amyloid aggregates) includes:

(1) coaggregation of essential cytoplasmic components,

(2) poisoning of the proteasome thereby inhibiting timely degradation of many cellular proteins,

(3) saturation of cytoplasmic chaperones that catalyze essential protein folding and refolding, and

(4) damaging mitochondria by aggregation onto the cytoplasmic surface and/or transport into the mitochondrial intermembrane space.