RICHARD J. SMEYNE, Ph.D.

Associate Member

Department of Developmental Neurobiology

St. Jude Children's Research Hospital and

Affiliated Associate Professor

Department of Anatomy and Neurobiology

The University of Tennessee College of Medicine

Address

St. Jude Children's Research Hospital

MS123, Roon D2025F

332 N. Lauderdale

Memphis, TN 38105

Tel: (901) 495-2830; Fax: (901) 495-3143;

Education

Ph.D. Institution: Thomas Jefferson University, Department of Anatomy, Philadelphia, PA

Postdoctoral: Roche Institute of Molecular Biology, Department of Neurosciences, Nutley, NJ

Research Interests

Parkinson's disease is a debilitating neurologic disorder that is characterized by a loss of pigmented neurons in the substantia nigra pars compacta (SNpc) and is probably caused by a multifactorial process involving an interaction of gene effects, subject age, and exposure to an environmental insult. In our lab, we used the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to recapitulate the pathology of human PD in mice. Previously, we found that the C57Bl/6J and SWR/J strains of mice differ in sensitivity to MPTP. By dissecting differences in the genome of these 2 strains of mice, we have identified a single quantitative trait loci (QTL) which theoretically contains the gene(s) that underlie sensitivity to MPTP. This QTL lies within the telomeric end of mChr. 1. We are now in the process of examining the genetic code in this region to uncover the specific genes responsible for MPTP susceptibility. Our lab is also studying which cells (neurons and/or glia) are responsible for the toxicity seen following MPTP administration. Using a novel chimeric culture method, we have found that the genotype of the glial cell plays a crucial role in determining whether an SNpc cell will die after exposure to MPTP. This finding may have implications for the development of novel therapies for the treatment of Parkinson's disease. In addition to discovering the gene(s) and cell types underlying experimental Parkinsonism, we are interested in examining novel methods of neuroprotection. We have found that exposure to an enriched environment (EE) can protect SNpc neurons from MPTP-induced cell death. Using quantitative PCR methods, we have shown that exposure to an EE increases the mRNA levels of BDNF, which has been shown to be neuroprotective in a variety of injury paradigms. In addition to our findings regarding neuroprotection, we have also shown that exposure to an EE can alter the anatomical structure of neurons in various regions of the CNS.

Another project in the lab examines the effects of prenatal exposure to drugs of abuse on developmental brain disorders, including deficits in neuronal and glial cell migration, motor performance, and environmental awareness. Exposure to these drugs in adults has been shown to cause memory defects and disorders of affect. Similar behavioral changes have been observed in animal models of drug abuse. Although the behavioral symptoms of prenatal and adult drug exposure have been described, few studies have examined the developmental mechanisms that underlie these behaviors. Drugs of abuse alter the levels of neurotransmitters in the brain, and changes in neurotransmitter levels can alter cell proliferation, cell migration, formation of neural connections, and cell survival. In the prenatal CNS, cells are generated in ventricular zones and migrate long distances to their final destinations. In the adult CNS, repopulation of neurons is severely limited; however, a few neurons are generated in the subventricular zone of the forebrain and either migrate through the rostral migratory stream to repopulate the olfactory bulb or migrate laterally to repopulate the hippocampus. We are using specific cell markers and computer-aided 3-dimensional reconstruction to trace the developmental migration of these cells. This work will allow us to determine the effects of prenatal or adult exposure to drugs of abuse on the development of the CNS. Related to cell survival, we are examining if mice prenatally exposed to cocaine have an increased sensitivity to drugs, such as MPTP or kainic acid, that effect abnormal release of neurotransmitters and induce cell death.

Links

St Jude Faculty - Richard J. Smeyne

Recent Publications

• Jang H, Boltz DA, Webster RG, Smeyne RJ. Viral parkinsonism. Biochim Biophys Acta. 2008 Aug 12; [Epub ahead of print] PMID: 18760350
• Wei P, Smeyne RJ, Bao D, Parris J, Morgan JI. Mapping of Cbln1-like immunoreactivity in adult and developing mouse brain and its localization to the endolysosomal compartment of neurons. Eur J Neurosci. 2007 Nov;26(10):2962-78. PMID: 18001291
• Boyd JD, Jang H, Shepherd KR, Faherty C, Slack S, Jiao Y, Smeyne RJ. Response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) differs in mouse strains and reveals a divergence in JNK signaling and COX-2 induction prior to loss of neurons in the substantia nigra pars compacta. Brain Res. 2007 Oct 17;1175:107-16. Epub 2007 Aug 9. PMID: 17884023
• Smeyne RJ. Catalog of the Neurological Mutants of Mouse revisited: honoring the 40th anniversary of its initial publication. Brain Res. 2007 Apr 6;1140:1. Epub 2007 Feb 6. No abstract available. PMID: 17288997
• Smeyne M, Boyd J, Raviie Shepherd K, Jiao Y, Pond BB, Hatler M, Wolf R, Henderson C, Smeyne RJ. GSTpi expression mediates dopaminergic neuron sensitivity in experimental parkinsonism. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1977-82. Epub 2007 Jan 31. PMID: 17267597
• Pattarini R, Smeyne RJ, Morgan JI. Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson's disease. Neuroscience. 2007 Mar 16;145(2):654-68. Epub 2007 Jan 29. PMID: 17258864

view complete list of references (pubmed link)