Project Grant R01NS134916

ASTROCYTE DYSFUNCTION IN SPINOCEREBELLAR ATAXIA TYPE 1 (SCA1) - ABSTRACT THE GOAL TO EFFECTIVELY TREAT NEURODEGENERATIVE DISORDERS REQUIRES AN UNDERSTANDING NOT ONLY OF NEURONAL DYSFUNCTION, BUT ALSO OF DYSFUNCTION OF NON-NEURONAL CELLS THAT CAN INITIATE AND CONTRIBUTE TO NEURONAL PATHOLOGY. SPINOCEREBELLAR ATAXIA TYPE 1 (SCA1) IS A FATAL, DOMINANTLY INHERITED NEURODEGENERATIVE DISEASE CAUSED BY THE ABNORMAL EXPANSION OF CAG REPEATS IN THE ATAXIN 1 (ATXN1) GENE. SCA1 PATIENTS SUFFER FROM PROGRESSIVE NEURONAL DEGENERATION AND REACTIVE ASTROGLIOSIS, ESPECIALLY IN THE CEREBELLUM, LEADING TO MOTOR DEFICITS. DESPITE INTENSE RESEARCH FOCUS ON THE DISEASE MECHANISMS IN CEREBELLAR NEURONS, THERE ARE NO EFFECTIVE THERAPIES AVAILABLE TO CURE, DELAY OR AMELIORATE SCA1. ASTROCYTES ARE BRAIN CELLS THAT PLAY FUNDAMENTAL ROLES IN NEARLY ALL ASPECTS OF NEURONAL AND BRAIN FUNCTION. RECENTLY, USING SINGLE-NUCLEI RNA SEQUENCING WE DEMONSTRATED THAT CEREBELLAR ASTROCYTES EXPRESS ATXN1 AT A LEVEL COMPARABLE TO NEURONS (BORGENHEIMER ET AL., 2022). THIS RAISES A QUESTION OF HOW MUTANT ATXN1 IN ASTROCYTES IMPACTS THEIR FUNCTION, CONTRIBUTES TO NEURONAL PATHOLOGY, AND LEADS TO SCA1-LIKE DISEASE OUTCOMES. TO FILL THIS KNOWLEDGE GAP, WE AIM TO DETERMINE THE MOLECULAR AND CELLULAR MECHANISMS THOUGH WHICH MATXN1 AFFECTS CEREBELLAR ASTROCYTES, AND HOW ASTROCYTE DYSFUNCTIONS CONTRIBUTE TO THE BEHAVIORAL AND PATHOLOGICAL CHANGES THAT ARE OBSERVED IN SCA1 DISEASE ONSET AND PROGRESSION.