self-propagating what kind of protein aggregates form the

self-propagating nature of prion amyloid aggregates,
similar to seeding under in vitro conditions,
is also shown by aggregates of the proteins in many age-dependent neurodegenerative
disorders including Alzheimer’s disease, Parkinson’s disease and the
tauopathies (Clavaguera et al., 2009; Brundin et al., 2010; Frost and Diamond, 2010; Goedert et al.,
2010; Kim and
Holtzman, 2010; Polymenidou
and Cleveland, 2011; Soto, 2012). These aggregates have the ability
to propagate across neuronal cells; however, the molecular mechanism behind the
prion-like behavior remains unclear (Brundin et al., 2010; Frost and Diamond, 2010; Lee et al., 2010). Hence, in many neurodegenerative
disorders, it appears that the prion-like behavior of misfolded and aggregated
proteins can account not only for the disease progression but also for the
propagation of these diseases (Goedert et al., 2010). However, it
remains unclear as to what kind of protein aggregates form the most infectious
material (Cohen and
Prusiner, 1998; Silveira et al., 2005; Diaz-Espinoza and Soto, 2012).

It
is now widely accepted that virtually all proteins can aggregate under specific
conditions, and form amyloid fibril-like structures (Dobson, 2003). Whether the protein
misfolding and aggregation propensity has any connection with disease or not,
many protein aggregates have been shown to have seeding abilities, at least,
under in vitro conditions. The
seeding ability of protein aggregates is the ability to abolish the lag phase
(nucleation phase), upon the addition of the preformed aggregates formed under
similar/different conditions. Increasing concentrations of the seed increase
the rate constant of polymerization, and completely abolishes the lag phase by
bypassing the nucleation step (Jarrett and
Lansbury, 1993; Collins et al., 2004; Cohen et al., 2012; Ramachandran and Udgaonkar, 2012). The seeding ability appears to be
an intrinsic feature of amyloid fibrils. Nevertheless, it is not yet clear
whether this seeding ability is a necessary criterion, in the case of disease-causing
proteins, for their cell-to-cell transmission and prion-like behavior in
disease conditions (Eisele et al., 2009; Polymenidou and Cleveland, 2012). If seeding
ability is a salient criterion for prion-like behavior, then virtually all
proteins, at least under in vitro
conditions, possess prion-like self-propagation behavior. Hence, the seeding
ability might be the primary mechanism by which an infectious agent propagates
to another cell or individual.

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Inhibitors
of amyloid aggregate-membrane interactions can be potential drug molecules
against protein misfolding diseases

Current
therapeutic strategies against prion diseases are based on the assumption that
PrPC converts into PrPSc, and consequently accumulates in
the central and peripheral nervous system. Based on this assumption, recent
therapeutic strategies include direct inhibition of prion conversion by either
stabilizing the monomer or blocking monomer-monomer interactions, degradation
or the clearance of PrPSc or by altering the expression and
localization of PrPC (Weissmann and
Aguzzi, 2005; Aguzzi et al., 2008b). Many studies
have attempted to develop immunotherapies against prion diseases, as antibodies
can prevent prion conformational conversion under in vitro conditions (Burchell and
Panegyres, 2016). Although immunotherapeutic
approaches can affect the accumulation of PrPSc in various parts of
the peripheral nervous system (Aguzzi and
Sigurdson, 2004), the ability to
prevent the progression of the diseases in the central nervous system is very
limited. The channel hypothesis has been proposed as a mechanism for amyloid-induced
cell toxicity (Kagan et al., 2004; Quist et al., 2005). Insights into the mechanism of
membrane poration caused by amyloid proteins will have implications in the design
of novel therapeutic molecules. Such therapeutic molecules can be used for
inhibiting pore formation, or for blocking the pore forming activity. Since the
middle hydrophobic region of the prion protein is known to play an important
role both in the productive association of PrPC with PrPSc
(Norstrom and
Mastrianni, 2005), and in the
prion protein-membrane interaction (Hegde et al., 1998; Bahadi et al., 2003; Sabareesan et
al., 2016), this region might be a potential
drug target for preventing prion mediated neurotoxicity. The possibility of
generating monoclonal antibodies against different regions of the prion protein
can be used for understanding the pathophysiology of prion diseases, and also
for obtaining passive immunization against prion diseases.

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