Project Grant F31NS139617

MICROGLIA- ASTROCYTE CROSSTALK IN CORTICAL NEURODEGENERATION OF C9ORF72 ALS/FTD - PROJECT ABSTRACT AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A PROGRESSIVE NEURODEGENERATIVE DISEASE CHARACTERIZED BY LOSS OF SPINAL CORD AND CORTICAL MOTOR NEURONS, AND FRONTOTEMPORAL DEMENTIA (FTD) IS AN EARLY-ONSET DEMENTIA SYNDROME CAUSED BY THE DEGENERATION OF THE FRONTAL AND TEMPORAL LOBES. THE MOST COMMON GENETIC CAUSE OF BOTH THESE DISEASES IS THE GGGGCC(G4C2) HEXANUCLEOTIDE REPEAT EXPANSION (HRE) IN THE FIRST INTRON OF THE C9ORF72. MUCH OF THE KNOWLEDGE IN C9ORF72-ALS/FTD DISEASE PATHOGENESIS THUS FAR HAS COME THROUGH INVESTIGATIONS OF NEURONAL DISEASE MECHANISMS. DESPITE THE LARGE EVIDENCE OF THE ACTIVE INVOLVEMENT OF GLIAL CELLS IN NEURODEGENERATION, LITTLE IS KNOWN ABOUT THE SPECIFIC MECHANISMS. ONE QUESTION THAT REMAINS UNANSWERED IS WHETHER A GLIA-GLIA INTERACTION IS REQUIRED TO INITIATE NEURODEGENERATION, OR DO ASTROCYTES AND MICROGLIA INDEPENDENTLY CONTRIBUTE TO THIS PROCESS? WE HAVE SHOWN AN ALTERED EXPRESSION PROFILE OF MICROGLIA AND ASTROCYTES IN THE FRONTAL CORTEX OF C9ORF72 ALS/FTD PATIENTS. ADDITIONALLY, IN OUR IPSC MODELING SYSTEM WE HAVE SEEN ABERRANT EXPRESSION OF THE NLRP3 INFLAMMASOME IN MICROGLIA AND ASTROCYTES. THESE FINDINGS LEAD TO THE FOLLOWING HYPOTHESIS: MICROGLIA- ASTROCYTE CROSSTALK UNDERLIES A CHRONIC PRO-INFLAMMATORY STATE IN C9ORF72 ALS/FTD. TO INVESTIGATE THIS KNOWLEDGE GAP, WE WILL UTILIZE STATE OF THE ART HUMAN IN VITRO CULTURE SYSTEMS, WHICH OFFER OPPORTUNITIES FOR EASY CELL-TYPE SPECIFIC MANIPULATIONS AND ANALYSES WHILE WORKING WITH HUMAN PATIENT-DERIVED CELLS. WE WILL UTILIZE MONO-CULTURE SYSTEMS TO ASSESS MORPHOLOGICAL, FUNCTIONAL, RNA, AND PROTEIN CHANGES. WE WILL VALIDATE OUR IN VITRO FINDINGS USING ALS/FTD PATIENT BRAIN TISSUES ON BOTH THE RNA AND PROTEIN LEVELS WITH THE INTENT OF UNDERSTANDING THE CELL-TO-CELL REGULATORY MECHANISMS OF GLIA AND THEIR CONTRIBUTION TO DISEASE PATHOLOGY. THESE STUDIES WILL PROVIDE NOVEL MOLECULAR TARGETS AND BIOMARKERS OF DISEASE.