Dopaminergic neurons in the substantia nigra of mouse brain (Labeled by IHC using TH anitbody)
RESEARCH PURSUITS
I. Stem cell contributions to Parkinson's disease
We have recently published our findings indicating use of stem cells for natural replenishment of dopaminergic neurons in the substantia nigra (the ones lost in PD) in adult mice. This may overturn a long-held belief that we are stuck with a fixed number of these neurons throughout life. As a result, this would designate dopaminergic neurons in the substantia nigra as one of a handful of neuronal populations found to experience neurogenesis in adult mammals. Our results also reveal that the rate of replenishment for these neurons is similar to the rate of loss observed in an inflammatory response mouse model of PD. This suggests that neurodegeneration in PD could, at least in part, be explained by inhibition of neurogenesis by inflammatory insult. Taken together, these results represent a major leap forward in our understanding of dopaminergic neuron biology and potential connections to Parkinson’s disease.
Our next goal is to characterize these neural stem cells to better our understanding of dopaminergic neurogenesis in adult animals. This information will aid in harnessing this natural replenishment process and better inform stem cell replacement therapies for treatment of PD.
Artist: Megan Llewellyn
II. Parkinson's disease and autophagy dysfunction
The primary clinical motor symptoms of PD result from loss of dopaminergic (DA) neurons in the substantia nigra, with autophagy dysfunction being closely linked to this disease. Autophagy is a cellular process responsible for degradation of organelles, macromolecules, and protein aggregates (such as the Lewy body depicted in the image to the right). In PD, characteristic toxic protein aggregates of primarily alpha-synuclein are believed to be substrates for autophagic removal. Clearance by autophagy improves preclinical model outcomes. Therefore, modulation of autophagy may be an effective strategy to combat PD. Recently, a PD-causing mutation in VPS35 (D620N) was reported to block autophagy. However, preliminary investigation by other groups into a causal mechanism was limited to canonical VPS35 protein interactors using a cervical cancer cell line (HeLa cells).
To overcome these limitations, we have performed an unbiased screen on a widely used PD cellular model using mass spectrometry and RNA sequencing (RNA seq) to identify key protein interactors and pathways. We are currently investigating affected pathways with the aim of identifying molecular targets to modulate autophagy specifically in dopaminergic neurons. Our ultimate goal is to modulate autophagy as a therapeutic strategy to rescue PD pathology.
III. Heightened inflammatory response in Parkinson's disease
Heightened inflammatory response coincides with neurodegenerative disease (ND). However, it is unknown if this is a causal or correlative association. To identify inflammatory factors that might confer predisposition to ND and substantiate a causal link, genetic linkage of inflammatory factors with ND loci were examined via the Pubmed OMIM database. It was discovered that the cytokine receptor IL-13RA1 lies in a PD locus and is expressed specifically in the substantia nigra and VTA (Allen brain atlas). Further analysis showed that mice lacking the IL-13RA1 gene were resistant to neuronal loss in a purely inflammatory model of PD, likely through decreased sensitivity to oxidative stress. Results from this investigation suggest that targeting IL-13RA1 signaling may have therapeutic potential for PD. We are currently targeting IL-13RA1 signaling for therapeutic intervention in PD.
