Proteasomes are very large protein complexes located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that carry out such reactions are called proteases. Proteasomes are part of a major cellular mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. Proteins are tagged for degradation with a protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is an polyubiquitin chain which can be bound by the proteasome, allowing it to degrade the tagged protein.The overall system of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome system (UPS). The proteasomal degradation pathway and, therefore the UPS, are essential for many cellular processes, including the cell cycle, the regulation of gene expression, and response to oxidative stress.Studies have shown that impairment of the ubiquitin-proteasome degradation system may play a role certain degenerative disorders of the nervous system, and specifically in Alzheimer's disease (AD) onset. Ubiquitin C-terminal hydrolase L1 (UCHL1) is an enzyme involved in the hydrolysis of polyubiquitin chains. It has been found that the quantity of UCHL1 is reduced in the brain of patients with AD.In a survey conducted by Oryzon Genomics on autopsied brains from Parkinson Disease and dementia with Lewy body (DLB) patients, we found that UCHL1 gene expression and protein levels were reduced in the affected brain areas. Therefore we looked for other genes and proteins able to restore the level of UCHL1. In this frame, we found that UCHL1 expression is regulated by another protein REST. REST is implicated in a protein complex (containing HDAC1, HDAC2, LSD1 and other components) involved in chromatin modification. The function of chromatin is, among others, to control gene expression and DNA replication. As a result of the discovery of role of the REST complex in the regulation UCHL1 levels and the importance of UCHL1 gene expression in AD, PD and other neurodegenerative diseases, we initiated a new approach to the treatment and prevention of neurodegenerative diseases based in drugs which are able to inhibit the activity of some of these proteins like LSD1.In the first experiments performed by Oryzon with these new candidate compounds in cell lines we detected augmented UCHL1 expression. Interestingly, we also discovered that these inhibitors caused a decrease in the levels expression of genes known to be implicated in AD, like BACE, ABCA1 and the ApoE gene. In the work relating to this grant, we aim to continue the development of these compounds culminating with the selection of two candidates for preclinical development. These candidates would then be profiled extensively for efficacy in different animal models while being evaluated in the appropriate regulatory preclinical studies required to obtain approval of an IND application allowing us to study these molecules in Human patients.