Project Grant R01AG082373

INTERSECTION OF GBA AND LRRK2 IN LEWY BODY DEMENTIA - LEWY BODY DEMENTIA (LBD) IS THE SECOND MOST COMMON FORM OF NEURODEGENERATIVE DEMENTIA, BEHIND ONLY ALZHEIMER'S DISEASE (AD). LBD IS CLINICALLY DEFINED AS A DEMENTIA THAT ARISES PRIOR TO OR WITHIN ONE YEAR OF A PARKINSON'S DISEASE (PD) DIAGNOSIS OR PD WITH SUBSEQUENT DEMENTIA. POST-MORTEM EXAMINATION OF LBD BRAINS COMMONLY REVEALS A COMBINED PATHOLOGY OF INTRANEURONAL LEWY BODIES ALONG WITH AMYLOID PLAQUES AND NEUROFIBRILLARY TANGLES CONSISTENT WITH AD. AS SUCH, LBD IS CONSIDERED ONE OF THE ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRDS). A SMALL SUBSET OF GENES IMPLICATED IN OTHER NEUROLOGIC DISEASES INFLUENCE RISK FOR LBD (E.G. GBA1, APOE), WHILE MANY GENES DETERMINANT FOR FAMILIAL FORMS OF AD OR PD DO NOT. THESE DATA SUGGEST A MEANINGFUL PARTIAL OVERLAP OF NEURODEGENERATIVE DISEASE GENES WITH REGARDS TO LBD. WHILE APOE HAS RECENTLY RECEIVED ATTENTION REGARDING ITS INFLUENCE ON BOTH AMYLOID AND ALPHA-SYNUCLEIN PATHOLOGY, GBA1 HAS NOT BEEN AS THOROUGHLY EXAMINED. AUTOSOMAL RECESSIVE MISSENSE MUTATIONS IN THE GBA1 GENE CAUSE THE LYSOSOMAL STORAGE DISORDER, GAUCHER'S DISEASE. INTRIGUINGLY, RECENT WORK DEMONSTRATES THAT GBA1 IS ALSO THE GREATEST RISK FACTOR FOR LBD. THE MOLECULAR MECHANISMS THROUGH WHICH GBA1 MUTATIONS MAY EVOKE THIS UNIQUE CLINICAL PRESENTATION AND COMPLEX NEUROPATHOLOGY ARE NOT KNOWN. OUR DATA DEMONSTRATE NOVEL GOLGI-RELATED DYSFUNCTION IN GBA1 MUTANT CELLS, UPSTREAM TO THE LYSOSOMAL AND LATE ENDOSOMAL EVENTS IMPORTANT TO ALPHA- SYNUCLEIN AND APP PROCESSING, RESPECTIVELY. HERE, WE WILL USE WILDTYPE INDUCED PLURIPOTENT STEM CELL-DERIVED NEURONS, AS WELL AS MATCHED ISOGENIC NEURONS HARBORING MULTIPLE PATHOGENIC GBA1 MUTATIONS, TO EXAMINE THE INFLUENCE OF GBA1 ON THE REGULATION, TRAFFICKING, AND MATURATION OF KEY LYSOSOMAL PROTEINS THOUGHT TO BE INVOLVED IN THE METABOLISM OF ALPHA-SYNUCLEIN. WE WILL ALSO EXAMINE THE RESULTING CHANGES IN ALPHA-SYNUCLEIN DEGRADATION AND NEURONAL RELEASE, AND THE ACCUMULATION OF ALPHA-SYNUCLEIN SPECIES RECENTLY DISCOVERED IN HUMAN LBD BRAIN TISSUE. IN ADDITION, THE EFFECT OF PATHOGENIC MUTATION IN GBA1 LINKED TO LBD ON GAMMA- SECRETASE AND APP BIOLOGY WILL BE MECHANISTICALLY AND PATHOLOGICALLY INTERROGATED HERE BOTH IN VITRO AND IN VIVO. LASTLY, EMERGING CLINICAL AND BIOCHEMICAL DATA DEMONSTRATE THAT GBA1 AND LRRK2 INTERACT IN BOTH PHYSIOLOGICAL AND DISEASE-RELEVANT WAYS. LRRK2 MUTATIONS CAUSAL FOR PD APPEAR TO DECREASE RISK OF DEMENTIA IN GBA1 PATIENTS. THUS, TO MODEL THESE DUAL-MUTATION CARRIERS, WE WILL EXAMINE NEURONS WITH GBA1 MUTATION ALONE OR THOSE ALSO EXPRESSING PATHOGENIC LRRK2 MUTATIONS AND ASSESS PATHWAYS RELEVANT TO SYNUCLEINOPATHY AND AMYLOIDOGENESIS DESCRIBED ABOVE. THIS WORK WILL DIRECTLY INVESTIGATE NOVEL PATHWAYS WITH THE POTENTIAL TO UNDERSTAND THE NOVEL CLINICAL PHENOTYPES AND MIXED AD/PD PATHOLOGY IN LBD. OUR APPROACH EXPLOITS THE GENETIC AND MOLECULAR INTERSECTIONS OF MULTIPLE NEURODEGENERATIVE DISEASES WITH THE GOAL OF UNDERSTANDING BOTH THE SIMILARITIES AND DIFFERENCES IN THEIR ETIOLOGIES.