To investigate mechanisms underlying the clinical observation that GBA1 mutations are associated with faster progression of motor and cognitive symptoms in Parkinson’s Disease (PD).

Mutations in the gene glucosidase, beta acid 1 (GBA1) are the strongest genetic risk factor for PD and are associated with accelerated disease progression. Our Drosophila GBA1 deficient model revealed alterations in exosomes which may act as vehicles to accelerate protein aggregate spread. We are elucidating how GBA1 deficiency influences endolysosomal trafficking and exosome biogenesis.

Expression of alpha-synuclein in flight muscle in Drosophila resulted in increased spread of oligomerized alpha-synuclein in the brain. GBA^IVS PD dopaminergic neurons have increased ubiquitinated proteins and larger early endosome and lysosome compartments compared to controls.  Preliminary results detected synuclein aggregates in EVs isolated from neuronal conditioned media.

Our Drosophila and human iPSC-neuron models support the hypothesis that GBA1 deficiency alters exosomes, which may mediate accelerated spread of Lewy pathology. We are now examining whether exosomes from GBA deficient neurons can propagate Lewy pathology more rapidly than exosomes isolated from control neurons. Understanding how GBA1 influences Lewy pathology spread could lead to new therapeutic targets to slow PD progression.