Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 42

the 52KO phenotype does include partial embryonic lethality. This combined with
the reproductive defects leads to difficulty in obtaining sufficient numbers of 52KO
animals for experiments. Thus, heterozygous fkbp52-deficient mice (52+/-) were
generated to determine the in vivo roles for FKBP52 in GR-mediated physiology.
52+/- mice displayed phenotypes associated with reduced GR signaling including
increased susceptibility to high-fat diet-induced hepatic steatosis, hyperglycemia,
hyperinsulinemia, and behavioral alterations under basal and chronic stress condi-
tions (Wadekar et al. 2004 ; Warrier et al. 2010 ).
Although FKBP52 does not alter ER function in cellular studies and 52KO mice
show no signs of estrogen insensitivity, FKBP52 expression is upregulated by es-
trogens and FKBP52 is over-expressed in breast tumors (Ward et al. 1999 ). In addi-
tion, the FKBP52 gene is methylated in ER-negative, but not in ER-positive breast
cancer cells (Ostrow et al. 2009 ). Thus, a few studies have identified FKBP52 as a
potential regulator of at least ER expression in breast cancer.
Despite the fact that FKBP52 was initially discovered in the immune system,
it is ubiquitously expressed and particularly abundant in the central nervous sys-
tem. Thus, it is not surprising that FKBP52 is involved in neurodegenerative
tauopathies including Alzheimer's (AD) and Pick's disease, fronto-temporal
dementia and Parkinsonism linked to chromosome 17 (FTDP), and progressive
supranuclear palsy (Haelens et al. 2007 ; Hernandez and Avila 2007 ). The defin-
ing neuropathological characteristic of tauopathies is the aberrant aggregation of
insoluble hyperphosphorylated microtubule-associated protein (MAP) tau within
the neurons, which is termed neurofibrillary tangles (NFTs) and is also referred to
as paired helical filaments (PHF) (Cao and Konsolaki 2011 ). Recent studies have
shown FKBP52's direct interaction with tau, particularly with its hyperphosphor-
ylated form, has antagonistic effects on tubulin polymerization and microtubule
assembly (Chambraud et al. 2007 ; Chambraud et al. 2010 ). In addition, FKBP52
was recently shown to induce Tau-P301L oligimerization and assembly into fila-
ments (Giustiniani et al. 2014 ). More importantly, knockdown of FKBP52 was
shown to restore axonal outgrowth and branching caused by Tau-P301L expres-
sion, thereby validating FKBP52 as an attractive therapeutic target in tauopathies.
FKBP52 is known to be involved in subcellular rearrangement. Studies by Quint￡
et al. demonstrated that the overexpression of FKBP52 can induce neuronal dif-
ferentiation and neurite outgrowth (Quint￡ et al. 2010 ).
Recent reports have shown that copper (Cu) contributes to the neuropathology
of AD by interacting with copper binding domains of amyloid precursor proteins
(APPs) and beta-amyloid (Aʲ) peptides causing the formation of amyloid plaques
and disrupting metal ion homeostasis (Barnham and Bush 2008 ; Drago et al. 2008 ;
Kong et al. 2007 ). FKBP52 is involved in the regulation of cellular Cu homeostasis
by interacting directly with the copper transport protein Atox1 (Sanokawa-Akakura
et al. 2004 ), which is part of the Cu efflux machinery in neurons. In addition, both
genetic and cellular data in Drosophila suggest a novel role for FKBP52 in the
regulation of intracellular Cu homeostasis via binding to APP, thus, modulating the
toxicity level of Aʲ peptides (Sanokawa-Akakura et al. 2010 ).