Carrettiero DC, Hernandez I, Neveu P, Papagiannakopoulos T, Kosik KS.
The cochaperone BAG2 sweeps paired helical filament- insoluble tau from the microtubule.
J Neurosci. 2009 Feb 18;29(7):2151-61.
PubMed.
This is an interesting set of results that seems to be suggesting that providing additional Bag2 somehow promotes a ubiquitin-independent proteasomal turnover of tau. I'm wondering how strongly expressed Bag2 might be in this context, relative to its basal level. Regardless, this is probing some interesting circuitry that deserves close attention.
This is a very informative paper from Carretierro et al. describing a novel relationship between BAG2 and tau. It further demonstrates the growing complexity of the chaperone network, moving us away from the idea that the chaperones are merely housekeeping genes that act in an unregulated, automated fashion. It seems that the route of tau clearance will be as complex, if not more complex, than the road to its hyperphosphorylation.
Members of the degradation process may also offer us more appropriate drug targets for therapeutic intervention in tauopathies and perhaps other diseases of protein misfolding. Identifying which chaperones are most specific for tau degradation could provide us with very novel clinical strategies for Alzheimer disease.
It should be noted that KNK437 does not inhibit Hsp70 activity but rather its levels via transcriptional repression of not only the Hsp70 gene, but also other heat shock genes (Yokota et al., 2000; Koishi et al., 2001). Changing the expression of Hsp70 levels could have very different consequences from directly inhibiting its ATPase function when clients are already bound.
One concern from many of these studies, including our own, is that the majority of models we work with overexpress tau. This is quite different from endogenous levels becoming dysfunctional, which is what occurs in human disease. It is quite possible that overexpressed chaperone clients, like tau, are processed quite differently from those that become dysfunctional at endogenous levels. Defining this could be critical for our understanding of the nature of chaperone biology in all protein misfolding diseases.
References:
Yokota S, Kitahara M, Nagata K.
Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells.
Cancer Res. 2000 Jun 1;60(11):2942-8.
PubMed.
Koishi M, Yokota S, Mae T, Nishimura Y, Kanamori S, Horii N, Shibuya K, Sasai K, Hiraoka M.
The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo.
Clin Cancer Res. 2001 Jan;7(1):215-9.
PubMed.
Comments
This is an interesting set of results that seems to be suggesting that providing additional Bag2 somehow promotes a ubiquitin-independent proteasomal turnover of tau. I'm wondering how strongly expressed Bag2 might be in this context, relative to its basal level. Regardless, this is probing some interesting circuitry that deserves close attention.
View all comments by Arthur HorwichDeceased, 2016
This is a very informative paper from Carretierro et al. describing a novel relationship between BAG2 and tau. It further demonstrates the growing complexity of the chaperone network, moving us away from the idea that the chaperones are merely housekeeping genes that act in an unregulated, automated fashion. It seems that the route of tau clearance will be as complex, if not more complex, than the road to its hyperphosphorylation.
Members of the degradation process may also offer us more appropriate drug targets for therapeutic intervention in tauopathies and perhaps other diseases of protein misfolding. Identifying which chaperones are most specific for tau degradation could provide us with very novel clinical strategies for Alzheimer disease.
It should be noted that KNK437 does not inhibit Hsp70 activity but rather its levels via transcriptional repression of not only the Hsp70 gene, but also other heat shock genes (Yokota et al., 2000; Koishi et al., 2001). Changing the expression of Hsp70 levels could have very different consequences from directly inhibiting its ATPase function when clients are already bound.
One concern from many of these studies, including our own, is that the majority of models we work with overexpress tau. This is quite different from endogenous levels becoming dysfunctional, which is what occurs in human disease. It is quite possible that overexpressed chaperone clients, like tau, are processed quite differently from those that become dysfunctional at endogenous levels. Defining this could be critical for our understanding of the nature of chaperone biology in all protein misfolding diseases.
References:
Yokota S, Kitahara M, Nagata K. Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells. Cancer Res. 2000 Jun 1;60(11):2942-8. PubMed.
Koishi M, Yokota S, Mae T, Nishimura Y, Kanamori S, Horii N, Shibuya K, Sasai K, Hiraoka M. The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo. Clin Cancer Res. 2001 Jan;7(1):215-9. PubMed.
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