The Role of HSP70 and Its Co-chaperones in Protein Misfolding, Aggregation and Disease - The Networking of Chaperones by Co-chaperones - page 251

the cooperation of HSP90 with the retina-specific HSP90 co-chaperone AIPL1, mu-
tations in which cause the devastating disease Leber congenital amaurosis (LCA)
characterised by the loss or severe impairment of vision at birth (Sohocki et al.
2000 ; Hidalgo-de-Quintana et al. 2008 ; Kolandaivelu et al. 2009 ). Therefore, de-
spite encouraging results in disease models, the clinical utility of these compounds
for the treatment of neurodegenerative diseases may be limited. Arimoclomol has
a superior pharmacokinetic profile and biodistribution in humans to bimoclomal
(Visy et al. 2002 ). Another important therapeutic consideration is that unlike other
HSR inducers, which induce the HSR in both unstressed and stressed cells, com-
pounds such as arimocolomal co-induce the HSR only under cellular stress condi-
tions (Hargitai et al. 2003 ).
As chaperones are fundamentally important in many essential cellular processes
it would not be surprising if pharmacological interference in their expression had
deleterious effects, although as yet none have been reported with arimoclomol.
Given the importance of Hsf-1 as the master regulator of chaperone gene transcrip-
tion and the limitations of global HSP90 inhibition, small molecules that directly
modulate Hsf-1 may be advantageous. A high-throughput screen for small mol-
ecule activators of Hsf-1 recently identified the compound HSF1A, a small ben-
zyl pyrazole-based molecule, which was shown to promote Hsf-1 activation in the
absence of HSP90 inhibition and did not induce undesirable proteotoxic activity
(Neef et al. 2010 ). HSF1A-mediated HSP induction reduced protein aggregates and
ameliorated polyQ-induced cytotoxicity in both a neuronal precursor cell and Dro-
sophila model of HD (Neef et al. 2010 ). Another therapeutic approach may be to
target specific co-chaperones, such as HSJ1 (DNAJB2) proteins, which have been
demonstrated to modulate protein aggregation, but are not ubiquitously expressed.
Mutations in Putative HSP70 Co-chaperones Which Cause
Inherited Disease
Multiple human disorders have been identified that are associated with mutations
in genes encoding chaperones or putative chaperones (Table 12.1 ). As yet, no mu-
tations associated with disease have been identified in HSP70 proteins, possibly
because these molecular chaperones are so fundamentally important to cellular
survival that mutations would be lethal. However, mutations in several HSP70 co-
chaperones have been identified as causing disease. The following is a brief de-
scription of some of these proteins.
The BiP Nucleotide Exchange Factor SIL1
In the lumen of the ER the HSP70 family member GRP78/BiP (HSPA5) plays a
crucial role in protein folding, protein translocation and quality control (Kleizen