Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) impact over 2 million people in the United States. Amyloid aggregates of α-synuclein in the cell body and axons, called Lewy pathology, characterize these diseases.
The goal of the lab is to determine how pathologic α-synuclein causes neuron dysfunction, leading to devastating symptoms including impaired movement, cognitive dysfunction, and psychiatric symptoms. The ultimate goal is to prevent damage to neuron function caused by abnormal α-synuclein, and restore brain circuitry to normal.
How do mutations in GBA1 and glycosphingolipids affect cognition? Heterozygosity for neuronotypic GBA1 mutations confers a 5X increase in risk of cognitive decline in PD. Pathologic α-synuclein is increased in the hippocampus, a brain region important for cognition, in mice heterozygous for GBA1L444P. Do increased levels of the lipid, glucosylsphingosine, caused by GBA1L444P play a role cognitive decline? We are testing novel pharmacologic compounds to reduce pathologic accumulation of glycosphingolipids to prevent cognitive decline in PD and Dementia with Lewy Bodies.
How does early formation of abnormal α-synuclein aggregates impact synaptic structure and function? We showed early formation of α-synuclein aggregates dramatically reduces dendritic spine density, yet paradoxically increases synaptic vesicle release. How do these early changes impact neuron function and brain circuitry contributing to PD and DLB symptoms? We are especially interested in corticostriatal and cortical-amygdala projections because of their role in non-motor symptoms of PD
How does LRRK2 influence α-synuclein? We are using live cell imaging and super-resolution microscopy techniques to determine how PD-associated LRRK2 influences synaptic localization and axonal transport of α-synuclein.