BCH3052 Lecture Notes - Lecture 11: Thioflavin, Neurodegeneration, Inclusion Bodies
25 May 2018
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Lecture 11 – Polyglutamine Repeat Proteins
Problems of Protein Folding
• Energy landscape is rough
• Poor folding fidelity
• Diseases associated with protein aggregation
o Most are sporadic (85%) and 10% are hereditary
o E.g. encephalopathy, Parkinson, alzheimers, Jakob disease
Amyloid Formation
• Misfolded monomer forms → amyloid fibril →
deposit
• Amyloid structure
o Cross beta structure (from x-ray)
o Bind congo-red and thioflavin T
o Sheets hydrogen bonded 4.7Å apart
o Core consists of all residues (7 peptide)
o Sequence dictates
▪ Length of strands
▪ Parallel vs antiparallel
▪ Length of loops and turns
• Amyloid can confer biological function
Kinetics of Fibril Formation
• Lag phase → rapid exponential phase
o Lag phase: time required for nuclei to form
o Addition of preformed nucleus shortens lag phase
Pathogenesis of Protein Deposition Disease
Loss of Function
Gain of Function
• A specific protein may be unable
to function because it is
incorrectly folded
• Misfolding may lead to incorrect
trafficking
• Aggregation leads to loss of
protein function
• Cellular function is impaired due
to interaction between aggregate
and cellular components
• Non-neurological amyloidosis are
due to large deposits of
aggregated protein in/around vital
organs
Stabilising Protein
• If understand structural basis can interfere
• Active as a tetramer → mutation causes problem in liver
• Aggregation can be inhibited – in the test tube
Polyglutamine Proteins and Disease
• E.g. Huntingtons, spinal bulbar muscular dystrophy
• Expansion of polyQ tract → neurodegenerative disease
• Formation of nuclear inclusions (NI) in neurons
• Neuronal dysfunction and death
• Onset: 30-50 years
• Severity and age of disease onset related to polyQ length
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