Disease relevance of Nmnat1

• Transected neurites in Nmnat1 transgenic dorsal root ganglion explant cultures also degenerated rapidly [1].

High impact information on Nmnat1

• Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene [2].
• The chimeric mRNA is abundantly expressed in the nervous system and encodes an in-frame fusion protein consisting of the N-terminal 70 amino acids of Ufd2, the C-terminal 302 amino acids of D4Cole1e, and an aspartic acid formed at the junction [3].
• Transfection of HEK293 cells with constructs comprising either full-length Nmnat-1 or the truncated Ube4b fragment (N70-Ube4b) demonstrated selective effects of Nmnat-1 (down-regulated pttg1) and N70-Ube4b (up-regulated edr1l-EST) on mRNA levels [4].
• The delay in vincristine-induced neurite degeneration following lentiviral overexpression of Nmnat1 was significantly less potent than for Wld(S), and lentiviral overexpressed enzyme-dead Wld(S) still displayed residual neurite protection [1].
• Whereas most NMN adenylyltransferase activity remained with the karyoplasts, glucose-6-phosphate dehydrogenase, ribonucleotide reductase, and thymidylate synthase were almost exclusively associated with the enucleated cytoplasts [5].

Biological context of Nmnat1

• The dominant slow Wallerian degeneration phenotype is conferred by a hybrid gene within the triplication, comprising a gene of previously unknown function, D4Cole1e, and the 5' end of ubiquitination factor E4B (Ube4b) [6].
• It encodes an in-frame fusion protein consisting of the N-terminal 70 amino acids of Ube4b and 303 amino acids derived from the D4Cole1e gene.We have identified the human homologue of D4Cole1e, and mapped it to chromosome 1p36 [6].
• The triplication has now been shown to be the causative mutation, acting through an Ube4b/Nmnat chimeric gene, indicating the possibility of Wld(S) preventing axon degeneration in diverse pathologies and altering the symptoms [7].
• Low nicotinamide mononucleotide adenylyltransferase activity in a tiazofurin-resistant cell line: effects on NAD metabolism and DNA repair [8].

Anatomical context of Nmnat1

• We generated transgenic Wld(S) rats expressing the Ube4b/Nmnat1 chimeric gene in the central and peripheral nervous system [9].
• Nmnat1 overexpression in five lines of transgenic mice failed to delay Wallerian degeneration in transected sciatic nerves in contrast to Wld(S) mice where nearly all axons were protected [1].
• Age-dependent synapse withdrawal at axotomised neuromuscular junctions in Wld(s) mutant and Ube4b/Nmnat transgenic mice [10].
• These results indicate that, under conditions where nuclear DNA synthesis is apparently unperturbed, the intracellular distribution of the deoxyribonucleotide biosynthetic enzymes studied is the same as that of glucose-6-phosphate dehydrogenase, a typical cytosol enzyme, and clearly differs from that of NMN adenylyltransferase, a nuclear enzyme [5].

Associations of Nmnat1 with chemical compounds

• There were no significant changes in NMNAT activity in response to MNNG treatment over 24 h, either in the presence or in the absence of NU1025 [8].

Regulatory relationships of Nmnat1

• The Wld s mice express both the normal and chimeric forms of ubiquitination factor E4 (Ube 4b) and nicotinamide mononucleotide adenylyltransferase-1 (Nmnat-1) [11].

Analytical, diagnostic and therapeutic context of Nmnat1

• The consequences of low cellular NAD levels in a cell line deficient in nicotinamide mononucleotide adenylyltransferase (NMNAT), an enzyme essential for NAD biosynthesis, were investigated by assessing NAD metabolism and DNA repair after treatment with alkylating agents [8].

References