skip to content »

Department of Neurology

Houston, Texas

BCM neurologists see patients through the Baylor Clinic and some of the world's leading specialty clinics.
Department of Neurology
not shown on screen

Current and Planned Research Projects

Based on our research strength and experience, we plan to pursue the following six main research themes in the next three years.

Basic Science Research

  1. Using the state of the art technology to search for novel PD-related genes and to investigate their interactions with genes known to be associated with parkinsonian disorders (e.g. interaction between Nurr1/NR4A2 and α-synuclein, parkin, UCHL1, DJ-1 and PINK-1), and to determine the modifying effects of environmental factors on genetic predisposition. We have identified two variants in Nurr1/NR4A2 gene, and demonstrated that the mutant genes linked to familial PD in Caucasian population. We have completed a screen of mutations of FMR1, PINK-1 and PACRG genes in over 250 patients with sporadic and familial PD. Three papers have been sent out for publication.

    Currently we have collected over 1,000 DNA specimens from patients with PD or other movement disorders. Using these genetic materials we plan to conduct PD linkage study to search for novel gene defects or find disease-associated loci. Since Nurr1/NR4A2 is a gene essential for dopamine neurons differentiation and maintenance, it is conceivable that this gene interacts with other PD-related nuclear and mitochondrial genes, or the gene may interact with environmental risk factors thus increasing the vulnerability of dopamine neurons leading to altered ubiquitin proteasome system and impaired dopamine transmission.
  2. We will continue to characterize the heterozygous Nurr1/NR4A2 knockout mice that we have first demonstrated to display age-dependent progressive dopamine neuron dysfunction resembling PD. Nurr1 gene, which codes for a transcriptional factor of nuclear receptor superfamily, plays an important role in the development of the mesencephalic dopaminergic system. In our previous studies we have found that the aged Nurr1/NR4A2+/- mice showed a significant decrease of locomotor activity and rotarod performance, suggesting that these mice have motor function impairment that may be analogous to parkinsonian deficit. We have further demonstrated that the abnormal behaviors in aged Nurr1/NR4A2+/- mice are associated with the decreased DA levels in the striatum and lower number of DAergic neurons in the nigra. Furthermore, we have documented that DA transporter (DAT) expression in the brain of aged Nurr1/NR4A2+/- mice are decreased. Our data indicate that Nurr1/NR4A2 is an important factor in maintaining nigral dopaminergic neuron function, and aged Nurr1/NR4A2+/- mouse is a useful animal model to study the pathogenesis of PD. Using this animal model we also plan to determine whether the predisposition of Nurr1 deficiency can enhance neuropathogenecity of proteasomal impairment by systematic treatment with proteasome inhibitor PSI in vivo. Results of this study will further support our theory that defects in genes associated with dopamine neuron development and function maintenance are important susceptibility factors contributing to PD.
  3. We will intensify our research to investigate the association between Nurr1/NR4A2 mRNA expression and PD. The purpose of this study is to determine whether the alteration of Nurr1 expression in human peripheral blood lymphocytes (PBL) can serve as a biological marker of dopaminergic function and may assist in early diagnosis of PD. So far we have measured Nurr1 mRNA levels by real-time RT-PCR in PBL from 121 PD patients, 56 healthy normal controls (NC) and 89 non-PD neurological disease controls. We have found that Nurr1/NR4A2 mRNA levels in PD/parkinsonism (n=128) are decreased by 79% vs NC (p<0.001). The comparison between PD and non-PD neurological disease controls in our preliminary study indicates a significant difference (p<0.01). A larger sampling study is under way, in witch we have collected over 300 PBL samples to study the specificity and sensitivity of the measurement of Nurr1/NR4A2 as a potential diagnosis assay for PD. We hope that the assay of Nurr1/NR4A2 mRNA in the PBL will become a clinical assay of biomarker for PD in the near future. The PCR conditions were optimized, the calibration was normalized, and corrected with internal and external standards according to requirement of Bio-Rad iCycler System (Bio-Rad). We have found that the specificity of primers and amplification, efficiency and sensitivity of the assay we are working are at the best condition we can get. We will calibrate and correct with internal and external standards each time we run the assay. The assay is very sensitive with liner range from 5 to 500 ng of total RNA and it is quite reliable with coefficient of variation within 10% range. To avoid the subjective errors, we plan to code all RNA samples blind to the investigator conducing the assay.
  4. We will continue to investigate the inflammatory/immune mechanisms in PD and search for anti-inflammatory/immune drugs for the therapeutic potential in PD. In the past 10 years, we have published over 10 original peer review papers (see the list of selected references) and made several important contributions in the field, including (a) a first experimental immune-mediated nigral injury animal model documented in guinea pigs, (b) finding of antibodies from PD patient sera can cause nigral injury, (c) demonstration that reactive microglia play an important role in the anti-body-mediated nigral injury and NO and hydroxyl radicals are the molecules responsible for the neuronal injury, and (d) illustration of protective effects of anti-inflammatory drug minocycline against nigral dopaminergic cell injury. We plan to screen new anti-inflammatory drugs to determine their ability to inhibit microglial activation and protect nigral cell injury.
  5. We will continue our mechanistic evaluation of PINK-1’s defect leading to mitochondrial dysfunction relevant to PD. First we will exploit a comprehensive linkage study of mitochondrial gene PINK-1 mutations or polymorphisms in PD. We will focus on the role of PINK-1 mutations or polymorphisms in dopamine neurons degeneration. Second, we will use RNA interference (RNAi) to inhibit gene expression that represents a powerful tool for exploring gene function and a powerful means to specifically knock-down a gene’s message and subsequently the protein level of the targeted gene. In our pilot study, interferencing PINK1 gene may result in apoptosis in SH-SY5Y cell. Third, we will study the interaction between genetic predisposition and environmental factors leading to dopamine neuron degeneration by using the two head insults of PINK1 RNAi with rotenone or MPP+ to induce apoptosis in SH-SY5Y cells. In this cell model we plan to determine whether Co-Q10, a mitochondrial stabilizer, can prevent such injury. Furthermore, we will also plan to test whether increase in glutathione reductase (GR) expression, an important antioxidant enzyme in the brain, can protect dopamine neurons against oxidative stress-induced cell injury and death in vitro and in vivo. We have generated a pRc/CMV/LGR-EGFP vector targeting mitochondria, and we have documented that CHO cells after transfected with the pRc/CMV/LGR-EGFP vector showed fluorescent signals in most of the cells and significantly increased GR activities in the mitochondrial fraction. Using this vector we plan (a) to transfect the GR gene in human dopamine cell line SH-SY5Y and determine whether increase in GR expression can protect 6-OHDA mediated cell injury in vitro; (b) to investigate whether enhancement of brain (substantia nigra) GR activities will protect against 6-OHDA induced PD phenotype.
  6. We will develop a Disease Modifying Therapy to target the pathogenesis pathways that cause PD. Currently we are studying Nurr1 gene activator that can enhance the transcriptional activity of the gene and lead to increase expression of dopamine neuron associated genes including tyrosine hydroxylase, dopamine transporter and vesicular monoamine transporter-2. The Nurr1 activator has been tested in MPTP mouse model and in Nurr1 deficient mouse model and the results of the behavioral and biochemical observation in these animal models demonstrate that the activator not only has strong antiparkinsonism potency and it also shows that long-term use of the compound can slow down the disease progression. We plan to study the detailed molecular mechanisms of Nurr1 in modifying the disease progression in vitro and in vivo and hopefully the new compound can be tested in patients with PD in the near future. In addition, we plan to investigate whether increase in chaperone (heat shock protein 70) expression can protect dopamine cell injury under various pathological conditions. The aims of the proposed study are: 1) to screen HSP70 inducible compounds; 2) to examine whether the compounds which may induce the HSP70 can protect against proteasomal inhibitor or rotenone (complex 1 inhibitor) induced mitochondria dysfunction leading to dopaminergic cell death. The third study for this project is to determine the role of autophage, a lysosomes system for protein degradation, in proteasome inhibition-induced neurodegeneration. By using lactacystin-induced neuronal death model which is considered to be relevant to PD model system, we try to provide proof-of-principle for the potential of inducing autophagy to slow or prevent the process of neuronal death in vitro and in vivo, which may lead to a further application of this strategy to PD. The fourth study is to focus on the impact of iron in the proteasome inhibitor-induced dopamine cell death and protein aggregation and to test whether new iron chelators can reduce the dopamine cell death and protein aggregation.
  7. We will continue our approach to use the genetically engineering adult mesenchymal stem cells (MSCs) to transform into dopaminergic neurons and test the ability of MSCs-derived dopaminergic neurons to restore dopaminergic function in vitro and in vivo. First, the highly purified MSCs will be transfected with HSV(LATP2)-mediated Nurr1 gene, a transcription factor critically important for the development and survival of midbrain dopaminergic neurons. Second, the genetically engineered MSCs will be induced into neurons by a panel of cytokines and inducible molecules. Third, to better control the expression of dopaminergic phenotype, a Geneswitch system will be constructed via the ligation of the full length Nurr1 at the multiple cloning site of pGen/V5-His, which can be turned on or off by mifepriston, a synthetic steroid binding with high affinity to the transacted hPR-LBD. Fourth, the functions of the MSCs-derived genetically engineered dopaminergic neurons will be tested in vitro and in 6-OHDA-lesioned animal model of PD in vivo. The outcome of the study will gain inside into the role of Nurr1 gene in dopaminergic neurons differentiation and provide molecular basis for generating genetically engineered and expression regulated dopaminergic stem cells. The ultimate aim of this study is to apply this novel therapeutic approach to treat PD.