Human RBM3 protein is prone to form neuronal aggregates opposed by the proteasome.

Maintenance of proteostasis is critical for neuronal functions, as the accumulation of misfolded or damaged proteins leads to neurodegeneration. Cooling is generally neuroprotective and is used in various clinical settings. However, how it impacts neuronal proteostasis remains unclear. In rodents, the neuroprotective effects of cold have been largely attributed to the cold-inducible RNA-binding motif protein 3 (RBM3). Here, studying the human RBM3 in cultured neurons subjected to profound hypothermia, we observed its cold-induced aggregation. These RBM3 aggregates are distinct from stress granules, occur specifically in differentiated neurons, and form also at physiological temperature upon proteasomal inhibition. Thus, in humans, RBM3 aggregation may be normally counteracted by the proteasome to maintain neuronal health. Exploring the natural variation between RBM3 proteins in hibernating versus non-hibernating mammals, we discuss how the aggregation could be prevented in animals with fluctuating body temperature. These findings are important for the understanding of RBM3 functions and neuronal proteostasis and have implications for medical treatments involving incidental and induced hypothermia.