Characterization of transgenic murine model overexpressing spermine oxidase (SMO)

Abstract

Natural polyamine (PAs), putrescine (Put), spermidine (Spd) and spermine (Spm) are positively charged aliphatic amines present in all tissues of almost all living organisms. The notion that PAs are absolute required for several cell functions has led to the study of their metabolism as a strategy for therapeutic interventions. Recently, efforts are addressed to understand the link between PAs and brain physiology. This interest originates from growing data indicating that PA metabolism is affected in several neurodegenerative disorders (Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, amyotrofic lateral sclerosis) or after neurotrama and cerebral ischemia. Spermine oxidase (SMO) is an enzyme involved in PA catabolic pathway; it oxidises Spm to produce Spd and two cytotoxic compounds: 3-aminopropanal and hydrogen peroxide. The SMO gene has been found to be highly expressed in the brain organ in physiological conditions, on the other hand its altered expression in some human organs is often associated to pathological disorders. Therefore, in this study I investigated whether SMO enzyme could play a role in the pathological status such as excitotoxic condition, found to be a common mechanism in neurodegenerative disorders. To this end, I exploited Dach: SMO mouse line which overexpresses SMO specifically in the brain cortex. Trangenic mice treated with kainic acid (KA) were more vulnerable to this neurotoxin and showed a higher neuronal cell death and gliosis and alteration of PA metabolism compared to syngenic controls. Moreover, in vitro study performed on corticostriatal slice cultures has suggested that SMO inhibition in excitotoxic condition could be partially neuroprotective. These data point out that SMO enzyme can be considered as a potential and additional therapeutic target against neurodegeneration induced by excitotoxicity.