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Amyloid in Health and Disease
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coli
Forms functional in fungi

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Amyloid Assembly
Amyloidogenic Precursors are Either Unfolded or Require Partial Unfolding
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Many amyloidogenic precursors are intrinsically unfolded in vitro e
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αsynuclein and β-amyloid peptides
Globular proteins can also form amyloid, but they require partial unfolding
Conditions that destabilise native structure, such as acidic pH, can
promote amyloid assembly by globular proteins
Mutations that destabilise the native structure of globular proteins can also
promote amyloid assembly and are associated with amyloid disease in
humans

β2-microglobulin Amyloid Formation
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β2-microglobulin forms amyloid in dialysis related amyloidosis
At pH 7, the wild type protein is very stable and does not aggregate to form
amyloid fibrils
In vitro, at acidic pH the native structure of β2-microglobulin is largely lost
and it readily forms fibrils
Removal of the N-terminal 6 residues of β2-microglobulin (proteolytic
cleavage not mutation) also destabilises the protein structure and enables
the protein to form amyloid at pH 7

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This truncated form of the protein is found in amyloid plaques and may
play a role in the initiation of amyloid formation in vivo

Mutations in Human Lysozyme are associated with Amyloidosis
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Human Lysozyme amyloidosis is associate with 2 point mutations in the
protein: Ile56Thr and Asp67His
The presence of these mutations destabilises the mainly α-helical native
structure and enhances amyloid formation

Amyloid Assembly is Nucleation Dependent
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Nucleation dependent assembly is characterised by a lag phase in which
fibrils are not observed
Fibril growth is observed during the subsequent exponential phase
Fibril growth begins once the nucleus is formed
Addition of preformed fibrils removes the lag phase

Oligomers are formed during Amyloid Assembly
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Soluble oligomeric species are produced during the lag phase of amyloid
assembly
Soluble oligomers are small aggregates formed by the amyloidogenic
precursor that are distinct from the insoluble fibrils
Oligomers may be intermediates in amyloid assembly, although some
oligomeric species may be formed by distinct assembly pathways
Oligomers are also of interest because they represent a major type of
cytotoxic species associated with amyloid disease

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Amyloid Diseases
Types of amyloid disease
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Over 20 different proteins/peptides form amyloid associated with human
disease
Some amyloid diseases are systemic with amyloid deposits forming at
multiple sites
Others diseases are localised with amyloid deposits forming in specific
sites
Localised amyloid formation in the brain is associated with
neurodegeneration
Neurodegenerative diseases
o Huntington’s disease
o Alzheimer’s
o Parkinson’s
o Prion disease
Systemic amyloid disease
o Dialysis related amyloidosis
o Lysozyme amyloidosis
o Transthyretin amyloidosis
Localised non-neuronal
o Amylin amyloidosis (Type 2 diabetes)

Dialysis Related Amyloidosis
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Dialysis related amyloidosis (DRA) is a complication of renal dialysis
β2-microglobulin (β2m) is a 99 amino acid protein that is normally removed
from the bloodstream by the kidney
In patients with renal failure, neither the kidney nor dialysis can remove
β2m efficiently from the bloodstream
β2m accumulates in the bloodstream and this predisposes patients to the
accumulation of β2m as amyloid plaques in the osteoarticular tissues
β2m amyloid deposition causes severe skeletal morbidity: bone cysts,
fractures, cartilage thinning
Renal transplantation is the best therapeutic option
In vitro, collagen and glycosaminoglycans (GAGs) promote amyloid
formation from β2m
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Functional Amyloid
Not All Amyloids Are Bad
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Amyloid can be a functional protein fold that does not cause pathology in
the organism that produces the amyloid
Functional amyloids have been identified in fungi, where fungal prions
(Sup35 and Het-S) act as non-genetic inheritable elements
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coli and salmonella
Curli fibres are extracellular and are composed of the protein CsgA
Curli promote biofilm formation, enabling bacteria to attach to surfaces
Curli fibres may also have a role in pathogenesis of E

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