The Department of Molecular and Cell Biology presents Matthew S. Goldberg, Ph.D., Assistant Professor, Department of Neurology and Neurotherapeutics and Department of Psychiatry, UTSW Medical Center at Dallas.
Mechanisms of Neurodegeneration in Parkinson’s Disease and Therapeutic Targets
Parkinson’s disease (PD) is a relentlessly progressive movement disorder leading to severe disability. The primary clinical symptoms are caused by loss of neurons in the substantia nigra that produce dopamine, which is required for normal movement. L-DOPA and related dopaminergic drugs can partially alleviate PD symptoms, however, there are currently no treatments proven to slow down or halt PD progression. The lack of disease-modifying therapeutics is primarily due to inadequate understanding of the pathogenic mechanisms and also due to the previous lack of pre-clinical animal models that reproduce the key features of PD, including normal development followed by spontaneous, age-dependent, and progressive loss of dopamine neurons selectively in the substantia nigra. The recent identification of mutations that cause inherited forms of PD provides opportunities to determine the cellular and molecular mechanisms of nigral cell loss and to test neuroprotective strategies.
Dominantly inherited mutations in LRRK2 are the most common cause of familial PD, and LRRK2 polymorphisms are associated with increased risk for the more common sporadic or idiopathic PD. The cellular function of LRRK2 is not certain; however, LRRK2 mutations are believed to increase the kinase activity of LRRK2 protein and cause cell death. We have identified key mechanisms that regulate LRRK2 oligomerization and subcellular localization that can be manipulated to mitigate the effects of LRRK2 mutations causally linked to PD. Loss-of-function mutations in the Parkin, DJ-1 and PINK1 genes cause recessively inherited PD. Our studies of mice and rats bearing similar deletion mutations in these genes reveal potential pathogenic mechanisms including mitochondrial dysfunction. PINK1 and DJ-1 knockout rats innately reproduce age-dependent locomotor behavior deficits and loss of over 50% of nigral dopamine neurons, which are the key features of PD. Our recently awarded NIH grants support our ongoing studies of PD pathogenesis and neuroprotective strategies using these knockout rats.
Refreshments will be served at 3:45 p.m. in FO3.606.