Mutations in ubiquilin 2 (Ubqln2) is linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. A foremost question regarding Ubqln2 pathogenesis is whether pathogenically mutated Ubqln2 causes neuron death via a gain or loss of functions. To better understand Ubqln2 pathobiology, we created Ubqln2 transgenic and knockout rats and compared phenotypic expression in these novel rat models. Overexpression of Ubqln2 with a pathogenic mutation (P497H substitution) caused cognitive deficits and neuronal loss in transgenic rats at the age of 130 days. In the transgenic rats, neuronal loss was preceded by the progressive formation of Ubqln2 aggregates and was accompanied by the progressive accumulation of the autophagy substrates p62 and LC3-II and the impairment of endosome pathways. In contrast, none of these pathologies observed in mutant Ubqln2 transgenic rats was detected in Ubqln2 knockout rats at the age of 300 days. Together, our findings in Ubqln2 transgenic and knockout rats collectively suggest that pathogenic Ubqln2 causes neuron death mainly through a gain of unrevealed functions rather than a loss of physiological functions.

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1 Oxide low-density lipoprotein (ox-LDL) is believed to play an important role in early events of atherogenesis, and asymmetric dimethylarginine (ADMA) is associated with the development of endothelial dysfunction. The present study examined the eect of a single injection of native lowdensity lipoprotein (LDL) on endothelium function and the serum level of ADMA and the eect of probucol on endothelium function and ADMA level in rats. 2Endothelial injury was induced by intravenous injection of LDL at the dose of 2, 4, or 6 mg kg 71 for 24, 48, or 72 h, and vasodilator responses to acetylcholine in the aortic rings and serum levels of ADMA, nitrite/nitrate (NO) and malondialdehyde (MDA) were determined. 3 Pretreatment with LDL markedly reduced endothelium-dependent relaxation in a concentrationdependent manner. Inhibition of vasodilator responses to acetylcholine by LDL was abolished in the presence of L-arginine (3610 74 M). Serum levels of ADMA and MDA were signi®cantly elevated in the rats pretreated with LDL, while serum level of nitrite/nitrate was markedly decreased. 4 Pretreatment with probucol signi®cantly improved endothelium-dependent relaxation, decreased concentrations of ADMA and MDA and increased nitrite/nitrate level in the rats treated with LDL. A similar eect was seen in the rats pretreated with an antioxidant vitamin E. 5 These results suggest that a single injection of native LDL causes endothelial dysfunction by elevation of ADMA levels and that the protective eect of probucol on endothelial cells is related to reduction of ADMA concentration.