The Lipid-Carrier Initiator Prion Hypothesis
In the Lipid-carrier initiator hypothesis, one may consider that prions form by occurrence of the following steps.
1. A charged, curved particle is present. Under
natural conditions, often this may be a negatively charged round
lipid particle, such as a lipid vesicle. We will term this the primary initiator.
A curved, charged lipid particle may be created by the presence of an
anion and lipids. For example, ribonucleic acid (RNA), or the
aluminosilicate mineral montmorillonite (Mte), when combined with
lipids, creates lipid vesicles. Other curved lipid particles are naturally present inside and outside of cells, serving a variety of functions.
2. A secondary portion of the initiator unit (we will use the term secondary initiator) may be present and bonds to or associates
with the target protein or the lipids in its vicinity, and
functions as an agent promoting conformational change.
For example, the secondary initiator may promote the final conformational change by disrupting and forming hydrogen bonds, hydrophobic or hydrophilic effects, increasing the disorder of the target protein structure, influencing local charge
interactions, increasing beta-sheet tendency or increasing the stability of an alternate folding conformation, and/or functioning as an
aggregant.
The target protein refers to the protein that becomes
misfolded and is commonly associated with the disease state, e.g. Prion
protein (PrP), A-beta, Alpha-synuclein, or superoxide dismutase 1
(SOD1).
3. The secondary initiator may be the assembler, carrier, or attractor of
the primary initiator round lipid particle. In fact, potential
examples of this seem to provide the most elegant and efficient natural
design.
For example, RNA or mineral (Mte) might act as secondary initiators, as they can
aggregate or bind prion protein, while also associating with lipid vesicles. Misfolded or mobile target proteins themselves may also fit these characteristics; for example prion protein PrPSc associates with lipid and also binds or interact with further PrP.
In this hypothesis, amphiphiles may also be considered as candidates for
secondary initiators. For example, ApoE4, a prominent risk factor for Alzheimer's disease, might act as a secondary
initiator. ApoE4 carries a lipid particle at one portion of the molecule. ApoE4 also has a portion that exhibits poor stability and
contains amino acids associated with tendencies toward beta-sheet
formation (2). According to this Lipid-carrier initiator hypothesis,
this portion of the apoE4 molecule could be considered as promoting conformational change and beta-tendency in the target protein upon interaction with the
target protein. The combined effects of the primary initiator lipid
particle that is carried by ApoE4 and the secondary initiator which has the
capacity to further interact with and change the shape of the target
protein, could produce the conformational change in the target protein.
By this process, a misfolded protein may be created.
4. The protein misfolding process described may be viewed as analogous
to the initiation step of a polymerization process, converting an original alpha-helical monomer into a polymerizable (activated)
beta-sheet form. As the process continues forward, further activations
result in polymer propagation, observed as fibril or plaque formation.