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6.9
Conclusions and Outlook
It is worth concluding this chapter with the central question: What
makes, by analogy to PrP aggregates, yeast prions “infectious” and
are other protein aggregates involved in human diseases, that are
similar in shape or by their secondary structure content, potentially
“infectious”? A partial answer to this question comes from the
observation that the vast majority of Ure2p and Sup35p homologues
that are expressed in various yeast strains and that possess Q/N
extensions do not, apart from a unique exception, induce [URE3] or
[PSI
+
107
In contrast,
a number of these homologues induce the prion phenotype when
expressed in
] phenotypes in their respective yeast strains.
108,109
S. cerevisiae
.
This suggests that
S. cerevisiae
is particularly suitable for, and sensitive to, infectious proteins
emergence and propagation, and might reflect a particular molecular
chaperone specific proteostasis in this yeast strain. The only protein
aggregates associated with disease, that are considered as infectious,
are those containing PrP. Recently, however, the cytoplasmic protein
aggregates enriched in fibrillar α-synuclein, known as Lewy bodies,
that are associated with Parkinson's disease, were shown to form in
healthy human fetal midbrain tissue transplanted into the brains of
Parkinson's diseased patients.
This observation suggests that the
aggregated α-synuclein, released from diseased neurons are capable
of “infecting” neighbouring healthy tissue. Similarly, other protein
aggregates associated with degenerative diseases such as Amyloid-
β, huntingtin, β2-microglobulin, and IAPP could play the role of
vectors in the formation of cytotoxic extracellular protein deposits
associated with Alzheimer's and Huntington's diseases, dialysis-
related and systemic amyloidosis propagation.
If this is indeed the case, then a wide variety of protein deposits
associated with disease would be infectious, that is, have prion
properties and could, through their aggregated state, propagate
phenotypes/diseases. What would distinguish these protein aggre-
gates from those we consider nowadays as prions is either their
capacity to recruit soluble polypeptide chains or their intrinsic
structural stability. Indeed, if the recruitment of the soluble form of
polypeptide A is less efficient by protein aggregate A than that of a
polypeptide B by protein aggregate B, aggregate A will grow slower
than B and will distribute less efficiently from mother to daughter
cells with, as a consequence, its loss during cell divisions. Similarly,
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