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Catalytic Prion-Like Cross-Talk between a Key Alzheimer’s Disease Tau-Fragment R3 and the Type 2 Diabetes Peptide IAPP
journal contribution
posted on 2019-11-05, 20:43 authored by Shruti Arya, Sarah L. Claud, Kristi Lazar Cantrell, Michael T. BowersThe aberrant association
of proteins/peptides is implicated in
the etiology and pathogenesis of a variety of human diseases. In general,
the primary protein component responsible for the formation of aggregates
is different in each case and is specific to a particular disease
condition. However, there are instances where multiple protein aggregates
have been found to coexist in the same or different tissue(s), thereby
leading to mixed pathologies and exacerbation of disease symptoms.
In this context, a strong link has been established between Alzheimer’s
disease (AD) and type 2 diabetes (T2D). However, the underlying molecular
details still remain elusive. Here, we report the direct interaction
of an AD-associated amyloidogenic cytotoxic fragment of Tau (R3:306–336)
with islet amyloid polypeptide (IAPP) implicated in T2D. Using ion-mobility
mass spectrometry (IM-MS) in conjunction with fluorescence spectroscopy,
circular dichroism, and transmission electron microscopy, we have
been able to provide critical mechanistic insights into these interactions.
Our IM-MS data showed the formation of hetero-oligomers of R3 and
IAPP. Additionally, using IM-MS, we found that the amyloidogenic extended
beta hairpin conformation of IAPP is favored much more in the R3-IAPP
mixture, when compared with IAPP alone. Furthermore, we found that
the oligomerization of R3 occurs much faster in the presence of IAPP.
We also observed a secondary nucleation step in our kinetics data
for the R3-IAPP mixture. We believe that the secondary nucleation
step is demonstrative of R3 aggregation which otherwise requires the
presence of anionic cofactors. Our results provide the first experimental
evidence for direct molecular interaction between Tau and IAPP and
highlights the repercussion of possible “prion-like”
cross-talk in the proliferation of diseases that are associated with
different tissues/organs.
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Keywords
R 3transmission electron microscopynucleation stepion-mobility mass spectrometryR 3-IAPP mixturetype 2 diabetesinteractionType 2 Diabetes Peptide IAPPCatalytic Prion-Like Cross-TalkT 2DIM-MSR 3 aggregationbeta hairpin conformationAD-associated amyloidogenic cytotoxic fragmentproteinislet amyloid polypeptide
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