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The long-term goal of my research is to understand the mechanisms of neuroprotection associated with Parkinson's disease (PD) and to identify and validate drug-targets for its therapy.

PD is a progressive neurodegenerative disorder characterized by the death of dopamine (DA) producing (dopaminergic -DAergic) neurons affecting an estimated 10 million people worldwide. The gradual depletion of DA eventually results frequently in tremor and in advancing symptoms of stiffness and slowing of movement.  Diverse environmental and genetic factors have been implicated in PD etiology yet, the etiology for the vast majority of PD cases remains unknown.

Current PD therapies replenish DA and improve symptoms while degeneration continues. Regrettably, chronic treatment causes dyskinesias, serious side effects, negating their benefits. Developing DA replacement therapies have had the advantage of relatively straight-forward assessment of efficacy due to the immediate improvement of patient symptoms. In sharp contrast, pharmacological strategies to develop neuroprotective therapies remain elusive partly because of the difficulty to assess their efficacy. The premise in my lab has been to discover and validate novel pharmacological targets for PD therapy. We thought that selection of an appropriate drug-target should 1) be linked with the of disease in humans, 2) be involved in several, if not all, mechanisms of disease pathogenesis 3) be amenable to therapeutic intervention, 4) be neuroprotective in a variety of pre-clinical PD models and 5) have the potential to provide evidence of efficacy in clinical trials.

We theorized that genes involved in DAergic fate determination may have functions beyond development and may be involved in PD pathogenesis. We focused on Nurr1, a nuclear receptor that turns-on the final differentiation of DAergic neuron precursors into the complete dopaminergic phenotype. We identified the first mutations in the Nurr1 gene in familial PD cases linking Nurr1 with the pathogenesis of PD (Nature Genetics, 33, 85). Our work indicated that Nurr1 expression levels are critical in developing the disease. The mutations map to the 5’ untranslated region of the gene and thus do not affect the protein but result in the decrease of Nurr1 steady state mRNA levels that, in turn, decrease tyrosine hydroxylase (TH) expression, the rate limiting enzyme in DA biosynthesis (Nature Genetics, 33, 85).

Decreased Nurr1 levels have been strongly associated with various aspects of PD pathogenesis and reduced DA-neuron survival. Nurr1 +/- mice have reduced striatal DA and are more susceptible to toxins such as MPTP, which inhibits mitochondrial function, the proteasome inhibitor lactacystin or alpha-synuclein overexpression (Human Molecular Genetics, 2020 under revision). Furthermore, Nurr1 knock-down in glia leads to exaggerated inflammatory responses that kill DA-neurons. 

We theorized that pharmacological activation of Nurr1 could halt the underlying pathology of PD. In DAergic neurons Nurr1 forms heterodimers with RXR. We designed BRF110, a unique in vivo active Nurr1:RXRα- heterodimer selective lead molecule, that binds to the RXRα-ligand binding pocket. BRF110 prevents DA-neuron demise and striatal DA-neuron denervation in vivo against PD-causing toxins affecting mitochondrial function and oxidative stress in a Nurr1-dependent manner. BRF110 also protects PD patient iPSC-derived DA-neurons against the PD-related genetic mutation LRRK2-G2019S and an alpha-synuclein mouse model against protein toxicity (PNAS 114, 3999).

Besides neuroprotection, BRF110 up-regulates the expression of the DA biosynthesis genes, TH, AADC, and GCH1, increases striatal DA in vivo and has symptomatic efficacy in two post-neurodegeneration PD models. Remarkably, chronic daily treatment of PD mice with BRF110 does not induce dyskinesias (PNAS 114, 3999). The combined neuroprotective and symptomatic effects of BRF110 on Nurr1:RXRα activation could provide a solution to the problems complicating disease modification efforts for PD, in that it is possible to have an indication of efficacy in clinical trials as there may be immediate symptomatic improvement.