Research

Parkinson's disease (PD) is a progressive neurodegenerative disease that causes a range of motor and non-motor symptoms. The two most striking pathological hallmarks of PD are the death of dopamine-producing neurons and clumps of aggregated protein called Lewy bodies in areas of neuronal loss. Lewy bodies are composed largely of the protein alpha-synuclein, though many recent studies also point to the presence of membranes and other lipids.

Currently, the only effective treatments for PD are symptomatic: they improve quality of life but do not slow or stop neuron loss. Collaborators at Brigham and Women's Hospital and Harvard Medical School identified promising drugs that break up alpha-synuclein clumps and prevent the death of cultured cells. Our lab has expanded upon these findings using an animal model that undergoes age-related dopamine neuron loss caused by alpha-synuclein. Through the use of genetic tools like CRISPR gene editing  and synthetic biology approaches like Auxin Inducible Degradation, we validated that disrupting these drug targets can save vulnerable neurons.

Ongoing work seeks to understand whether the neuroprotection we have seen is associated with a preservation of function. Are the spared neurons healthy and still able to do their jobs? We are also trying to understand whether changes in lipids underlies the neuroprotection we see in our model. We hope that our work may one day lead to disease modifying treatments for people with PD.

Sensation, behavior, and cognition all depend on the proper formation and function of neuronal connections called synapses. Synapses that use the chemical glutamate as a neurotransmitter to signal between nerve cells are the most abundant type in our central nervous system. Glutamate synapses are highly dynamic, and their restructuring provides the cellular basis of learning and memory. Failure to properly form or maintain glutamate synapses can lead to disorders like schizophrenia, autism spectrum disorders, or Alzheimer’s disease.

In order for these synapses to function properly, glutamate receptors on downstream cells need to be transported to the cell surface from internal storage compartments called endosomes. Our previous work showed that disruption of C. elegans proteins VER-1 and VER-4, which are homologous to VEGFRs in people, interferes with the intracellular transport of a glutamate receptor called GLR-1 and weakens neuronal communication.

Ongoing work seeks to understand whether VERs regulate the trafficking of multiple types of glutamate receptors, determine what specific steps in the transport process are affected, and identify ways in which neurons controls VER expression. Understanding how the strength of glutamate synapses is controlled can help illuminate cellular processes and molecular pathways that go awry in the context of neurological disorders. This research could also provide insight into the mechanisms of synaptic restructuring during learning and memory.