The Li Lab focuses on 1) understanding how mutations in the gene LRRK2 lead to damage to dopamine-producing neurons in familial Parkinson’s disease and 2) screening potential drugs for Parkinson’s.
Parkinson’s disease (PD) is a chronic, progressive disorder that affects nerve cells (dopaminergic (DA) neurons) in the region of the brain called the substantia nigra. These neurons produce dopamine, a signaling chemical (neurotransmitter) that allows us to walk, speak and feel in our daily life. DA neurons in the substantia nigra project a pathway to another part of the brain called the striatum, and this nigrostriatal dopaminergic pathway is responsible for coordinating and controlling body movement. When these neurons degenerate and die, as they do in Parkinson’s patients, dopamine levels fall, thus interfering with the way muscles work and compromising the patient’s ability to easily initiate movement. A current treatment for these symptoms is dopamine replacement therapy, in which Parkinson’s patients are given dopamine precursors that are converted into dopamine by cells in the brain.
Genetic mutations have been identified to contribute to the onset and progression of PD, and the most common mutations linked to PD are in the LRRK2 gene. It remains largely unknown how LRRK2 mutations lead to the development of PD. We previously established that expression of mutant LRRK2 in aged preclinical models causes symptoms similar to what are observed in PD patients. This provides us with the ability to see when the dopaminergic neurons degenerate and where this degeneration is initiated on the molecular and cellular levels. These models also allow us to interrupt disease progression at early stages, with the aim of developing therapeutics for Parkinsonism.
Our lab is focused on investigating the functional changes of LRRK2 mutants in the preclinical models, including our genetic and neurotoxin models. We utilize a variety of methods to understand how LRRK2 mutations affect LRRK2 functions at the molecular and cellular levels, and thus understand how these functional changes contribute to the progression of PD. Elucidation of the molecular mechanisms underlying LRRK2 parkinsonism will provide novel insight into PD progression, and facilitate development of a cure.
Another important aspect of our research is to screen drugs in both chemical toxic models and genetic models of Parkinson’s disease, with the aim of identifying neuroprotective drugs against neurodegeneration in PD and transforming these potential drugs into bedside use.
The following are current, ongoing projects within the Li Lab: (1) Dissection of the molecular mechanism of LRRK2 Parkinsonism We are determining the LRRK2 signaling pathways by identifying the interactive partners and/or downstream effectors of LRRK2 with a variety of biochemical and cellular biology approaches. We are pursing how and where the LRRRK2 signaling initiated the degeneration of DA neurons. (2) Identification of potential drugs for Parkinson’s. We are testing potential prodrugs in the MPTP neurotoxic model and find the drugs that can store/preserve the DA neurons in the nigrostriatal pathways.