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2017 ; 11
(ä): 254
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The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases
#MMPMID28559789
Lackie RE
; Maciejewski A
; Ostapchenko VG
; Marques-Lopes J
; Choy WY
; Duennwald ML
; Prado VF
; Prado MAM
Front Neurosci
2017[]; 11
(ä): 254
PMID28559789
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The accumulation of misfolded proteins in the human brain is one of the critical
features of many neurodegenerative diseases, including Alzheimer's disease (AD).
Assembles of beta-amyloid (A?) peptide-either soluble (oligomers) or insoluble
(plaques) and of tau protein, which form neurofibrillary tangles, are the major
hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client
maturation, but they also target misfolded or aggregated proteins for refolding
or for degradation, mostly by the proteasome. They form an important line of
defense against misfolded proteins and are part of the cellular quality control
system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays
a major part in this process and it is well-known to regulate protein misfolding
in a variety of diseases, including tau levels and toxicity in AD. However, the
role of Hsp90 in regulating protein misfolding is not yet fully understood. For
example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans
model of A? misfolding leads to increased toxicity. On the other hand, the use of
Hsp90 inhibitors in AD mouse models reduces A? toxicity, and normalizes synaptic
function. Stress-inducible phosphoprotein 1 (STI1), an intracellular
co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly,
STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In
addition to its intracellular function, STI1 can be secreted by diverse cell
types, including astrocytes and microglia and function as a neurotrophic ligand
by triggering signaling via the cellular prion protein (PrP(C)). Extracellular
STI1 can prevent A? toxic signaling by (i) interfering with A? binding to PrP(C)
and (ii) triggering pro-survival signaling cascades. Interestingly, decreased
levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In
this review, we will discuss the role of intracellular and extracellular STI1 and
the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in
neurodegenerative diseases, with particular focus on AD.
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