D-amminoacidi nella malattia Alzheimer (con un focus speciale sul catabolismo del D-aspartato)

D-Serine (D-Ser) and D-aspartate (D-Asp) act as neuromodulators of N-methyl-D-aspartate receptors, which are involved in several neuropsychiatric pathologies, including Alzheimer’s disease (AD). To clarify whether these molecules are deregulated in AD, serum levels of Ser and Asp enantiomers were determined by HPLC. The obtained results indicated a significant correlation between D-Ser level and AD, allowing to propose this parameter as a novel biomarker for AD diagnosis. In humans, little is known about D-Asp metabolism: its synthetic pathway is still unclear while the flavoenzyme D-aspartate oxidase (DASPO) is known to be responsible for its degradation. The studies carried out during my PhD project aimed at shedding light on the processes modulating the cellular levels and activity of DASPO, and possibly controlling brain D-Asp. In particular, I focused on two isoforms of the human enzyme constituted by 341 and 369 amino acids: their functional properties and the mechanisms involved in protein turnover were investigated by their ectopic expression in a human cell line. These studies demonstrated that both isoforms are active, localize to the peroxisomes, are highly stable and primarily degraded through the ubiquitin-proteasome system. I also evaluated the effect of specific post-translational modifications on the properties of the enzyme: human DASPO can be in vitro nitrosylated and sulfhydrated, although both modifications do not seem to affect its catalytic activity