FIG. 5.

Evidence supporting either a direct neuroprotective or neurotoxic function of RBM3, CIRBP, or RTN3 in the brain. Literature on RBM3, CIRBP, and RTN3 was obtained via PubMed. All articles were screened via an initial abstract review. A secondary search via Google was done to identify any additional articles not referenced in PubMed. Studies using in vitro neuronal injury paradigms (cell lines or primary neurons) or in vivo brain injury/disease models were analyzed in-depth (i.e., if available). One article was in Chinese and converted to English using Google translate. Purely observational studies were identified and excluded. This figure incorporates studies that (1) overexpressed, (2) knocked down, or (3) incubated neuronal cells/tissues with a recombinant CSP (or any combination of the three) in vitro and/or in vivo, to generate a direct conclusion germane to a given CSP protective versus detrimental function(s). For the purpose of this review, we did not rate the “quality of the evidence” but noted that the scientific rigor varied considerably across studies. Top: findings were organized into “Battlefield Boxes,” which summarize the opposing sides of evidence that support either neuroprotective (blue region) or neurotoxic (red region) roles of CSPs. White dots indicate individual studies and each is aligned with the year of publication. Stacked dots indicate multiple studies published in the same year. A total “Score” was given (large white numbers on the right side of the squares), which is the sum of all studies that supported either protective or detrimental functions of each CSP. The literature epoch spans approximately two decades from 2002 to 2019. Bottom: an overview of the diverse cell signaling mechanisms reported to mediate neuroprotective versus neurotoxic effects of CSPs. The proposed mechanisms are based on the experimental data presented by articles shown in the Battlefield Boxes. All articles are cited in the main text, and also listed here in order of publication date. RBM3: Kita et al., Chip et al., Zhu et al., Peretti et al., Yang et al., Bastide et al., Zhuang et al., Yang et al., Xia et al. CIRBP: Saito et al., Li et al., Rajayer et al., Zhou et al., Liu et al., Zhang et al., Li et al., Zhang et al., Wang et al., Chen et al. RTN3: Hu et al., Shi et al., Shi et al., Chen et al., Shi et al., Teng and Tang, Araki et al., Shi et al., Sharoar et al., Bastide et al., Zou et al. CIRBP, Cold inducible RNA binding protein; RTN3, reticulin-3.