My lab’s interest is in understanding the contributions of stem cell activity, autophagy dysfunction, and heightened inflammatory response to neuronal loss in Parkinson’s disease (PD) so that targeted therapies can be developed. The clinical motor features of PD arise from the loss of dopaminergic (DA) neurons in the substantia nigral region of the brain. However, the molecular mechanisms underlying this neuronal loss are currently unknown. As a result, no effective treatments currently exist that address neurodegeneration in PD.
Artist: Megan Llewellyn
Our Latest Parkinson's Disease Research
Our lab has discovered evidence for the replenishment of dopaminergic neurons in adult mice. This finding may overturn the long-held notion that these neurons cannot be regenerated through endogenous processes within PD patients. What’s more, we have uncovered that the generation rate of these neurons in adult mice is similar to what has been reported for loss of these neurons in inflammatory models of PD. This suggests that inflammatory insult may be facilitating the loss of these important neurons, thereby leading to development of PD. This insight will aid in crafting stem cell replacement therapies.
Extending upon our findings that dopaminergic neuron progenitors exhibit a similar expression profile to that of endothelial cells (Nestin+, dopaminergic) and could possibly arise from a quiescent pool of post-mitotic cells (Sox2-), we explored the possibility that transdifferentiation of endothelial cells could explain adult neurogenesis of dopaminergic neurons in the mouse substantia nigra. We discovered that removal of an enzyme responsible for dopamine synthesis (tyrosine hydroxylase) from endothelial cells in adult mice later resulted in a loss of this enzyme from dopaminergic neurons. This is consistent with an endothelial cell origin for dopaminergic neurons in adult mice (and possibly humans). We are actively investigating this possibility and we have uncovered a number of other disease-relevant cell types that also appear to exhibit a profile consistent with endothelial transdifferentiation using a different cell lineage tracing strategy.
Endothelial Cell Transdifferentiation Research
Understanding the contribution of endothelial cells to the progenitor pools of adult tissues has the potential to inform therapies for human disease. To address whether endothelial cells transdifferentiate into non-vascular cell types, we performed cell lineage tracing analysis using transgenic mice engineered to express a fluorescent marker following activation by tamoxifen in vascular endothelial cadherin promoter-expressing cells (VEcad-CreERT2; B6 Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze). Activation of target-cell labeling following 1.5 months of ad libitum feeding with tamoxifen-laden chow in 4-5 month-old mice resulted in the tracing of cerebellar granule neurons, ependymal cells, skeletal myocytes, pancreatic beta cells, pancreatic acinar cells, tubular cells in the renal cortex, duodenal crypt cells, ileal crypt cells, and hair follicle stem cells. As Nestin expression has been reported in a subset of endothelial cells, Nes-CreERT2 mice were also utilized in these conditions. The tracing of cells in adult Nes-CreERT2 mice revealed the labeling of canonical progeny cell types such as hippocampal and olfactory granule neurons as well as ependymal cells. Interestingly, Nestin tracing also labeled skeletal myocytes, ileal crypt cells, and sparsely marked cerebellar granule neurons. Our findings provide support for endothelial cells as active contributors to adult tissue progenitor pools. This information could be of particular significance for the intravenous delivery of therapeutics to downstream endothelial-derived cellular targets.
Our Latest Autism-Spectrum Disorder Research
Our investigations into adult neurogenesis of dopaminergic neurons have uncovered surprising results that have prompted us to question fundamental assumptions regarding mammalian biology. One of these assumptions centers upon how a cell coordinates the transition (differentiation) from one cell type to another. Such a transition requires an orderly degradation of existing proteins while allowing for new proteins to be produced. The most widely adopted belief is that proteins within a cell are targeted for degradation by E3 ubiquitin ligases via conserved protein sequences. However, given an estimated ~20,000 protein-encoding genes in the human genome, alternative mRNA spicing and post-translational modifications, the proteome is mathematically near infinite. The conserved domain theory is not consistent with this evidence. Therefore, we developed a novel unbiased mass spectrometry-based screening approach to identify post-translational protein modifications that could better explain the mechanism for en masse protein turnover during cellular differentiation. This work has uncovered strong evidence for a rare protein modification that directs degradation of target proteins without the need for a conserved protein sequence. Interestingly, we have identified the enzyme that likely facilitates this modification and it is very closely associated with autism-spectrum disorder (ASD). A major hallmark of ASD is altered neuronal differentiation which provides further credence for this study. We also observe a dramatic change in protein expression for this enzyme during cellular differentiation. Our future goals are to modulate the expression of this enzyme to enhance or inhibit cell differentiation and alter ASD mouse model outcomes.