The Co-chaperone BAG2 Mediates Cold-Induced Accumulation of Phosphorylated Tau in SH-SY5Y Cells
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Inclusions of phosphorylated tau (p-tau) are a hallmark of many neurodegenerative disorders classified as “tauopathy,” of which Alzheimer’s disease is the most prevalent form. Dysregulation of tau phosphorylation disrupts neuron structure and function, and hyperphosphorylated tau aggregates to form neurotoxic inclusions. The abundance of ubiquitin in tau inclusions suggests a defect in ubiquitin-mediated tau protein degradation by the proteasome. Under the temperature of 37 °C, the co-chaperone BAG2 protein targets phosphorylated tau for degradation via by a more-efficient, ubiquitin-independent pathway. In both in vivo and in vitro studies, cold exposure induces the accumulation of phosphorylated tau protein. The SH-SY5Y cell line differentiates into neuron-like cells on treatment with retinoic acid and is an established model for research on the effects of cold on tau phosphorylation. The aim of the present study was to investigate whether BAG2 mediates the cold-induced accumulation of phosphorylated tau protein. Our findings show that cold exposure causes a decrease in BAG2 expression in undifferentiated cells. Conversely, BAG2 expression is increased in differentiated cells exposed to cold. Further, undifferentiated cells exposed to cold had an increased proportion of p-tau to total tau, suggesting an accumulation of p-tau that is consistent with decreased levels of BAG2. Overexpression of BAG2 in cold-exposed undifferentiated cells restored levels of p-tau to those of 37 °C undifferentiated control. Interestingly, although BAG2 expression increased in differentiated cells, this increase was not accompanied by a decrease in the proportion of p-tau to total tau. Further, overexpression of BAG2 in cold exposed differentiated cells showed no significant difference in p-tau levels compared to 37 °C controls. Taken together, these data show that expression of BAG2 is differently regulated in a differentiation-dependent context. Our results suggest that repression of BAG2 expression or BAG2 activity by cold-sensitive pathways, as modeled in undifferentiated and differentiated cells, respectively, may be a causal factor in the accumulation of cytotoxic hyperphosphorylated tau protein via restriction of BAG2-mediated clearance of cellular p-tau.
KeywordsTemperature Cold exposure Hypothermia Differentiation Cell Tauopathy Alzheimer’s disease
The authors with to acknowledge extramural financial support provided by FAPESP (Grant, 2009/11446-4, 2011/06528-1 and 2012/50336-2) and CNPq (449102/2014-9) as well as financial support from CAPES and UFABC intramural funds.
C. A. D. P., M. C. A. and D. C. C. contributed to design of experiments. C. A. D. P., F. E. S., A. S. A. O., and F. A. O. performed experiments. Analysis of experimental data was done by C. A. D. P., F. E. S., M. C. A., and D. C. C. The manuscript was prepared by C. A. D. P., F. E. S. and D. C. C.
Compliance with Ethical Standards
Conflict of Interest
The authors declare no competing interests.
- Abramoff M, Magelhaes P, Ram S (2004) Image processing with ImageJ. Biophotonics Int 11:36–42Google Scholar
- McLaughlin D, Tsirimonaki E, Vallianatos G, Sakellaridis N, Chatzistamatiou T, Stavropoulos-Gioka C, Tsezou A, Messinis I, Mangoura D (2006) Stable expression of a neuronal dopaminergic progenitor phenotype in cell lines derived from human amniotic fluid cells. J Neurosci Res 83:1190–1200CrossRefPubMedGoogle Scholar
- Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13:703–714CrossRefPubMedGoogle Scholar
- Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A (2004) Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer’s disease. J Neurosci 24:2401–2411CrossRefPubMedGoogle Scholar
- Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J, White CL 3rd, Mumby MC, Bloom GS (1999) Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J Biol Chem 274:25490–25498CrossRefPubMedGoogle Scholar
- Whittington RA, Bretteville A, Virag L, Emala CW, Maurin TO, Marcouiller F, Julien C, Petry FR, El-Khoury NB, Morin F, Charron J, Planel E (2013) Anesthesia-induced hypothermia mediates decreased ARC gene and protein expression through ERK/MAPK inactivation. Sci Rep 3:1388CrossRefPubMedPubMedCentralGoogle Scholar