Briana De Miranda, PhD
Name of Institution:
University of Alabama at Birmingham, Birmingham, AL
Cdk5 inhibition as a protective mechanism against environmental toxicant induced Parkinson’s disease
Dr. De Miranda is a neurotoxicologist and Assistant Professor at the Center for Neurodegeneration and Experimental Therapeutics (CNET) in the Department of Neurology at the University of Alabama at Birmingham (UAB). Her research is focused on environmental risk factors associated with neurologic disorders, including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), Alzheimer’s disease (AD), and related dementias.
Dr. De Miranda received her PhD in Toxicology from Colorado State University and trained as a postdoctoral fellow at the University of Pittsburgh with Dr. J. Timothy Greenamyre. Her interdisciplinary background in neuroscience and toxicology laid a foundation to assess mechanisms of neurotoxicity from exposure to environmental contaminants. She also has a background using gene-therapy and pharmacologic approaches to prevent neurodegeneration in experimental models of toxicant exposure. Her current research is centered on mechanisms of neurodegeneration caused by the organic solvent and PD risk factor trichloroethylene (TCE), using environmentally relevant experimental models of exposure.
To measure if inhibition of a specific kinase protein, cyclin dependent kinase 5 (Cdk5), can protect against PD pathology induced by environmental exposures linked to PD risk.
PD risk is linked to environmental exposures and industrial byproducts such as trichloroethylene (TCE), which can induce dopaminergic cell death. However, there are no therapeutic approaches designed to prevent neurodegeneration from toxic chemicals. Our experimental data in mice show that TCE not only causes death of dopaminergic neurons, but also induces other PD pathologies such as the accumulation of phosphorylated a-synuclein and Tau. In addition to these co-pathologies, we found that TCE raises the activity of kinase protein Cdk5, which is associated with aberrant protein phosphorylation in PD and AD. Thus, targeting Cdk5 could be a therapeutic strategy to attenuate PD progression.
The lab has developed an innovative method of TCE exposure in rodents that replicates human-like passive inhalation of TCE vapor over extended periods. The project will use two approaches to inhibit Cdk5 and assess whether this protection against TCE-induced neurodegeneration and PD co-pathology. The first approach involves using a viral vector to knockdown Cdk5 in dopaminergic neurons of the substantia nigra (SN), and the second approach employs a novel biologic called TP5, which selectively inhibits aberrantly activated Cdk5 when administered systemically.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
As most PD cases are idiopathic (unknown cause), the outcomes of these neurotoxicity studies can apply to almost all PD cases. Furthermore, under-represented and disadvantaged communities with limited access to healthcare are disproportionately at higher risk for environmental exposures linked to PD risk. This work may have a significant impact on these communities burdened with greater exposure. Cyclin dependent kinase inhibitors, like what we are studying, are in clinical trials for certain cancers, making the findings of this research even more promising as future treatments.