Peretti D, Bastide A, Radford H, Verity N, Molloy C, Martin MG, Moreno JA, Steinert JR, Smith T, Dinsdale D, Willis AE, Mallucci GR. RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature. 2015 Feb 12;518(7538):236-9. Epub 2015 Jan 14 PubMed.
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Overall, this study is interesting and extends previous work in this field. A role for RBM3 in protection against cell death under conditions of hypothermia had been fairly well established previously by other groups (e.g. Chip et al., 2011; Tong et al., 2013). Now the authors intend to carry this research further, putting it into the framework of neurodegenerative disorders such as prion disease and Alzheimer´s disease (AD). In doing so, they completely ignore a specific pathology of AD, namely hyperphosphorylation of tau. As we showed for quite a variety of small and large species of hibernators, such as European ground squirrels, Syrian hamsters, Arctic ground squirrels, and the Black bear, synaptic regression during hibernation is associated with AD-like hyperphosphorylation of tau in neurons which lose their afferentation (Arendt et al. 2003; Härtig et al., 2007; Stieler et al., 2009; Stieler et al., 2011; Arendt and Bullmann, 2013). This hyperphosphorylation is completely reversible after arousal of the animals, in conjunction with re-establishment of synaptic connectivity. Since the authors now suggest RBM3 as a potential therapeutic target for neurodegenerative disorders, including AD, it would be essential to analyze potential effects on the specific pathology of these disorders such as tau-phosphorylation. Furthermore, the potential impact of this study on our understanding of neurodegenerative disorders, and on the identification of new therapeutic targets, is limited by the fact that an involvement of RBM3 in human pathology remains to be shown. The current study is restricted to animal work, which makes it difficult to judge its potential value for human CNS disorders.
References:
Chip S, Zelmer A, Ogunshola OO, Felderhoff-Mueser U, Nitsch C, Bührer C, Wellmann S. The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection. Neurobiol Dis. 2011 Aug;43(2):388-96. Epub 2011 Apr 17 PubMed.
Tong G, Endersfelder S, Rosenthal LM, Wollersheim S, Sauer IM, Bührer C, Berger F, Schmitt KR. Effects of moderate and deep hypothermia on RNA-binding proteins RBM3 and CIRP expressions in murine hippocampal brain slices. Brain Res. 2013 Apr 4;1504:74-84. Epub 2013 Feb 8 PubMed.
Arendt T, Stieler J, Strijkstra AM, Hut RA, Rüdiger J, Van der Zee EA, Harkany T, Holzer M, Härtig W. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci. 2003 Aug 6;23(18):6972-81. PubMed.
Härtig W, Stieler J, Boerema AS, Wolf J, Schmidt U, Weissfuss J, Bullmann T, Strijkstra AM, Arendt T. Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons - implications for Alzheimer's disease. Eur J Neurosci. 2007 Jan;25(1):69-80. PubMed.
Stieler JT, Bullmann T, Kohl F, Barnes BM, Arendt T. PHF-like tau phosphorylation in mammalian hibernation is not associated with p25-formation. J Neural Transm. 2009 Mar;116(3):345-50. PubMed.
Stieler JT, Bullmann T, Kohl F, Tøien Ø, Brückner MK, Härtig W, Barnes BM, Arendt T. The physiological link between metabolic rate depression and tau phosphorylation in mammalian hibernation. PLoS One. 2011;6(1):e14530. PubMed.
Arendt T, Bullmann T. Neuronal plasticity in hibernation and the proposed role of the microtubule-associated protein tau as a "master switch" regulating synaptic gain in neuronal networks. Am J Physiol Regul Integr Comp Physiol. 2013 Sep;305(5):R478-89. PubMed.
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