{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nStudies indicate that TMEM246‐AS1 (a transcript associated with the NRH2/NRADD gene) plays a key regulatory role in neurotrophin receptor signaling. In particular, it appears to be involved in modulating the cell surface presentation of co‐receptors that determine neuronal sensitivity to proneurotrophins. One study showed that the p75 neurotrophin receptor homologue, NRH2, enhances the trafficking of sortilin to the plasma membrane by interacting with its cytoplasmic domain, thereby facilitating the formation of receptor complexes that trigger neuronal apoptosis upon proneurotrophin binding."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn another set of investigations, a homologous protein known as p45 – which shares structural similarities with NRH2 – was found to engage in heterodimer formation with p75, interfering with its role as a co‐receptor for the Nogo receptor. This interaction, mediated by both transmembrane cysteine residues and death domains, blocks downstream RhoA activation and mitigates the inhibitory effects of myelin-associated proteins on neurite extension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional findings reveal that p45 can also associate with the adaptor protein FADD, thereby diminishing Fas‐mediated apoptotic signaling. Moreover, genetic deletion of NRADD leads to alterations in the proportion of dorsal root ganglion neurons expressing p75, underscoring a delicate balance in neurotrophin signaling that may impact survival versus death decisions. These insights suggest that TMEM246‐AS1, through its linkage with NRH2/NRADD and related splice variants, could serve as an important regulatory molecule in neuronal response to both injury and neurodegenerative stimuli."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Taeho Kim, Barbara L Hempstead "}, {"type": "b", "children": [{"type": "t", "text": "NRH2 is a trafficking switch to regulate sortilin localization and permit proneurotrophin-induced cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2009.118"}], "href": "https://doi.org/10.1038/emboj.2009.118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19407813"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19407813"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mark Murphy, Yvette M Wilson, Ernesto Vargas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Aging (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neurobiolaging.2014.09.014"}], "href": "https://doi.org/10.1016/j.neurobiolaging.2014.09.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25443284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25443284"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marçal Vilar, Tsung-Chang Sung, Zhijiang Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterodimerization of p45-p75 modulates p75 signaling: structural basis and mechanism of action."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pbio.1001918"}], "href": "https://doi.org/10.1371/journal.pbio.1001918"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25093680"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25093680"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Tsung-Chang Sung, Zhijiang Chen, Sandrine Thuret, et al. "}, {"type": "b", "children": [{"type": "t", "text": "P45 forms a complex with FADD and promotes neuronal cell survival following spinal cord injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0069286"}], "href": "https://doi.org/10.1371/journal.pone.0069286"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23935974"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23935974"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Nicolas Unsain, Genevieve Dorval, Jae Hyung Sheen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Generation and characterization of mice bearing null alleles of nradd/Nrh2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genesis (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvg.22989"}], "href": "https://doi.org/10.1002/dvg.22989"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27775873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27775873"}]}]}]}