MECHANISMS OF NEURODEGENERATION AND NOVEL THERAPEUTIC TARGETS IN TAUOPATHIES

ALZHEIMER’S DISEASE (AD) AND OTHER TAUOPATHIES PRESENT ABNORMAL FUNCTION AND AGGREGATION OF TAU PROTEIN, FORMING INTRACELLULAR NEUROFIBRILLARY TANGLES (NFT). IN SPITE OF DEPOSITS OF BETA AMYLOID PEPTIDE ALSO FOUND IN AD, NFTS BETTER CORRELATE WITH CLINICAL DEMENTIA AND SEVERITY, AND ARE CLOSELY LINKED TO NEURONAL DEATH. SEVERAL TAU POST-TRANSLATIONAL MODIFICATIONS ARE KNOWN TO PROMOTE ITS AGGREGATION AND LOSS-OF-FUNCTION BEFORE CELL DEATH OCCURS, INCLUDING ITS PHOSPHORYLATION, UBIQUITINATION, OR CLEAVAGE BY CASPASES. HOWEVER, HOW THESE MODIFICATIONS ARE REGULATED AND THEIR CONTRIBUTION TO THE NEURONAL DEATH AND TO THE OVERALL PATHOLOGY PROGRESSION ARE QUESTIONS THAT REMAIN TO BE ANSWERED. WE HAVE EVIDENCES THAT THE NEURONAL ANTI-APOPTOTIC PROTEIN FAIM-L (FAS APOPTOSIS INHIBITORY MOLECULE) MAY BE INVOLVED IN THIS REGULATORY PROCESS. FAIM-L NORMALLY AVOIDS THE DEGRADATION OF XIAP, BY PREVENTING ITS UBIQUITINATION; THIS WAY, IT ALLOWS THE INHIBITION OF CASPASE 3 AND CONSEQUENTLY, NEURONAL APOPTOSIS. FAIM-L ALSO PARTICIPATES IN THE REGULATION OF NON-APOPTOTIC CASPASE 3 FUNCTIONS, INCLUDING DENDRITIC PRUNING AND SYNAPTIC PLASTICITY, FOUND ALTERED IN TAUOPATHIES. FAIM-L HAS ALSO BEEN DEMONSTRATED TO POSSESS ANTI-AGGREGATING CAPACITIES. WE HAVE OBSERVED THAT FAIM-L LEVELS ARE REDUCED IN BRAINS OF AD PATIENTS AND IN AD MOUSE MODELS PRESENTING TAU PATHOLOGY. IN ADDITION, OUR IN VITRO PRELIMINARY DATA INDICATE THAT TAU AND FAIM-L INTERACT, AND THIS PREVENTS TAU UBIQUITINATION, ASSOCIATED TO PATHOLOGIC BUT ALSO PHYSIOLOGIC TAU FUNCTIONS. THUS, WE HYPOTHESIZE THAT, THROUGH MODULATION OF ITS UBIQUITINATION, FAIM-L CAN REGULATE TAU FUNCTIONS AND MODIFICATIONS LEADING TO ITS AGGREGATION AND RELATED PATHOLOGY, AND THEREFORE, RESTORING FAIM-L LEVELS MAY PREVENT NEURONAL DEATH ASSOCIATED TO TAU PATHOLOGY. OUR AIMS ARE TO UNRAVEL THE ROLE OF FAIM-L ON TAU PHYSIOPATHOLOGICAL MECHANISMS AND TO TEST FAIM-L AS A NEW THERAPEUTIC TARGET FOR THESE DISORDERS. TO REACH THESE OBJECTIVES, WE WILL USE IN VITRO APPROACHES WITH NEURONAL IMMORTALIZED CELL LINES AND NEURONAL PRIMARY CULTURES TO ASSESS THE PHYSIOPATHOLOGICAL ROLE OF TAU AND FAIM-L RELATIONSHIP. IN ADDITION, FAIM-L LEVELS WILL BE CHECKED IN HUMAN BRAIN TISSUE FROM DIFFERENT DISEASES PRESENTING TAU PATHOLOGY TO EXPLORE WHETHER FAIM-L IS ALTERED IN A BROADER DISEASE SPECTRUM. FINALLY, THE THERAPEUTIC EFFECT OF FAIM-L WILL BE DETERMINED IN THE P301S TAUOPATHY MOUSE MODEL, WHERE WE WILL INDUCE FAIM-L OVEREXPRESSION IN THE HIPPOCAMPUS OF 6 MONTHS OLD MICE; THEN, CHANGES IN THE PATHOLOGY PROGRESSION WILL BE EVALUATED BY COMPARISON WITH MICE WITH DECREASED FAIM-L LEVELS THROUGH BEHAVIORAL AND MEMORY TESTS, DETERMINATION OF THE SYNAPTIC ACTIVITY, AND ANALYSIS OF NEUROPATHOLOGICAL AND BIOCHEMICAL PARAMETERS. THE RESULTS OBTAINED WILL PROVIDE A BETTER UNDERSTANDING OF TAU DYNAMICS IN PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS AND HOPEFULLY, WILL ALLOW PROPOSING FAIM-L AS NOVEL THERAPEUTIC TARGET NOT ONLY FOR AD BUT ALSO FOR OTHER TAUOPATHIES.