Second year undergraduate essay written for the Cell Pathology module of the Biomedical Sciences course at the University of Oxford.
Essay title: What is known of the molecular basis of human diseases characterized by protein misfolding?
Very helpful for tutorial preparation and exam revisio...
What is known of the molecular basis of human diseases characterized by protein
misfolding?
Proper functioning of proteins depends on their distinct three-dimensional structures, so
abnormal conformations adopted by misfolded proteins lead to various diseases.
Pathological conditions can result from protein misfolding in two major ways, either loss-of-
function as misfolded proteins are rendered non-functional, or toxic gain-of-function. In this
essay, we focus on discussing the latter mechanism in pathogenesis of degenerative
diseases involving formation of toxic amyloid aggregates, but it is important to note the
ongoing controversy although well-supported theories around the topic have been
established.
To begin with, proteins can adopt a multitude of different conformational states and are
capable of being converted into non-functional and potentially damaging protein
aggregates. Accumulation of misfolded proteins into amyloid fibrils is associated with a
range of pathologies depending on the type of protein affected and the target tissues. For
example, deposition of amyloid plaques formed from misfolded amyloid-β peptide (Aβ) in
the central nervous system (CNS) causes Alzheimer’s disease (AD), which is the most well-
studied neurodegenerative diseases. Parkinson disease is believed to be caused by
aggregation of α-Synuclein (αs) amyloids, whereas non-neuropathic diseases such as type II
diabetes is associated with aggregation of islet amyloid polypeptide. Most amyloid deposits
are secreted into the extracellular space but some remain intracellular and form
intracellular inclusions. Despite originating from different proteins, amyloid-related
degenerative diseases share numerous pathological features, evidences also indicate that
amyloids share common structural properties that are largely determined by generic
polymer properties.
It has been hypothesized that protein misfolding diseases share a common pathogenesis
mechanism since amyloid formation does not seem to depend on protein species. When
proteins misfold, attraction between exposed hydrophobic amino acid residues cause
proteins to aggregate into small soluble oligomers, they act as intermediates for the
formation of insoluble amyloid fibrils when polypeptide elongates and intermolecular
hydrogen bonds form. These fibrils have cross-β structures, defined by β-strands running
perpendicular to the long-fibril axis, and their formation is an inherent property of
polypeptide chains. To support, Fandrich and Dobson (2002) found that polyamino acids like
poly-L-lysine were able to form fibrils, they concluded that aggregation depend on main
chain interactions rather than polypeptide sequences. Oligomers of different proteins share
a common structure as shown by Kayed and Head et al. (2003) who observed that a
conformation-dependent antibody specifically recognizes a shared epitope on amyloid
oligomers of different proteins but not their fibrils or other amyloid intermediates. The
common amyloid structures proved by these experiments suggest a shared mechanism of
toxicity in different protein misfolding diseases.
Although amyloid fibrils represent an end-product of protein aggregation, it is increasingly
accepted that oligomers are the key common pathogenic species in protein misfolding. The
oligomer hypothesis was proposed by Lambert in 1998, based on the discovery that fibril-
free synthetic preparations of Aβ oligomers were potent CNS neurotoxins that inhibited
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