Hsp90 activity is necessary to acquire a proper neuronal polarization

Abstract

Chaperones are critical for the folding and regulation of a wide array of cellular proteins. Heat Shock Proteins (Hsps) are the most representative group of chaperones. Hsp90 represents up to 1-2% of soluble protein. Although the Hsp90 role is being studied in neurodegenerative diseases, its role in neuronal differentiation remains mostly unknown. Since neuronal polarity mechanisms depend on local stability and degradation, we asked whether Hsp90 could be a regulator of axonal polarity and growth. Thus, we studied the role of Hsp90 activity in a well established model of cultured hippocampal neurons using an Hsp90 specific inhibitor, 17-AAG. Our present data shows that Hsp90 inhibition at different developmental stages disturbs neuronal polarity formation or axonal elongation. Hsp90 inhibition during the first 3h in culture promotes multiple axon morphology, while this inhibition after 3h slows down axonal elongation. Hsp90 inhibition was accompanied by decreased Akt and GSK3 expression, as well as, a reduced Akt activity. In parallel, we detected an alteration of kinesin-1 subcellular distribution. Moreover, these effects were seconded by changes in Hsp70/Hsc70 subcellular localization that seem to compensate the lack of Hsp90 activity. In conclusion, our data strongly suggests that Hsp90 activity is necessary to control the expression, activity or location of specific kinases and motor proteins during the axon specification and axon elongation processes. Even more, our data demonstrate the existence of a "time-window" for axon specification in this model of cultured neurons after which the inhibition of Hsp90 only affects axonal elongation mechanisms.

Heat Shock Proteins Regulatory Role in Neurodevelopment

“…This hypothesis is further supported by the observation that inhibition of Hsp90 results in reduced membrane translocation of the growth factor tyrosine receptor kinase A (TrkA) in human acute myeloid leukemia cells ( Rao et al, 2010 ). Interestingly, in this study, inhibition of Hsp90 was associated with an increase in Hsp70, which could reflect a compensatory response similar to what was described by Benitez et al (2014) . Although additional studies are necessary to further understand the specific functions of Hsps in cell growth, collectively, these studies clearly support an important role for Hsps in tumorigenesis, as well as normal development.…”

“…Interestingly, one recent study has shown that Hsp90 is required for key events in neuronal polarization. Using neurons isolated from moues embryos at E17, Benitez et al (2014) showed that pharmacologic inhibition of Hsp90 with the Hsp90 inhibitor, 17-demethoxygeldanamycin (17-AAG), both disturbs neuronal polarization and slows axon elongation. In addition, these perturbations were accompanied with a reduction in PI3K/Atk/GSK3 signal transduction.…”

“…Independent of development, such challenging environments are strongly associated with the stress-inducible Hsps, suggestive of a potential role for these proteins also during neurodevelopment. Indeed, recent studies have uncovered that individual Hsps directly regulate neurodevelopment itself through modulation of pathways involved in cell growth and migration, such as the PI3K/Akt and RhoA signaling cascades ( Konishi et al, 1997 ; Sato et al, 2000 ; Hennessy et al, 2005 ; Dou et al, 2007 ; Banz et al, 2009 ; Wang et al, 2012 ; Sun et al, 2013 ; Benitez et al, 2014 ).…”

HSP90 is a chaperone for DLK and is required for axon injury signaling

“…In future studies, it will be interesting to identify any remaining HSP90 clients within the context of axon injury. HSP90 has established roles in other neuronal contexts, namely the stabilization of neurodegenerative protein aggregates, but also, in neuronal polarization, axon pathfinding, and neurotransmitter release (58)(59)(60)(61). Here, we describe a role for HSP90 in axon injury signaling and synapse growth.…”

Decreased expression of human heat shock protein 70 in the endometria and pathological lesions of women with adenomyosis and uterine myoma after GnRH agonist therapy

“…Molecular chaperons are critical for the folding and regulation of a wide array of cellular proteins (3). Heat shock proteins are the most representative group of chaperons.…”