Mechanisms of Neurodegeneration and Neuroprotection

Figure 1: Expression of EMT(red) in various
mouse brain regions.

1) Glial-Neuronal Interaction: In recent years, it has increasingly been recognized that the abundance of astrocytes, their strategic organization, and close proximity to neurons provide good opportunities for intercellular exchange of molecules between these two cell types. However, the mechanism and the extent to which astrocytes are involved in regulating the levels of neurotoxic cations and thereby affecting neurodegeneration are largely unknown. One of our current projects is designed to test the hypothesis that astrocytes play a dual role in preventing and inducing neurodegeneration by regulating the levels of toxic cations available to neurons through the extraneuronal monoamine transporter (EMT).

(2) Mitochondrial Dysfunction:

Figure 2: Blockade of the electron transport chain (A)
or release of the apoptogenic molecules (B) may lead
to cell death.

The pathogenic role of mitochondrial dysfunction in PD and HD has been quite well established and, in light of the recent discoveries of the genetic mutations in PD, has emerged as a topic of great interest. Dysfunction in the mitochondrial electron transport chain, the releases of mitochondrial apoptogenic molecules (as illustrated in Figure 2) and dysregulation in mitochondrial dynamics, would potentially lead to neuronal dysfunction and death.

Our experimental approach is to use both pharmacological agents and genetic manipulations in both in vivo and in vitro models of PD and HD. Major techniques available in the lab include: Cell cultures, stereotaxic surgery, in vivo microdialysis, HPLC, stereology, confocal imaging,
immunohistochemistry/immunocyto-
chemistry, and other standard
molecular biology methods
such as immunoblotting and RT-PCR.

Selected Publications

Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, Jackson-Lewis V, Javitch JA, Ballatori N, Przedborski S, Tieu K. The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci U S A. 2009 May 12;106(19):8043-8048.

Zhou H, Falkenburger BH, Schulz JB, Tieu K, Xu Z, Xia XG. Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci. 2007 Mar 5;3(4):242-250.

Tieu, K. Mitochondrial dysfunction and neurodegenerative disorders in the basal ganglia. In: Recent breakthroughs in basal ganglia research. Erwan Bezard (editor). New York: Nova Science Publishers. 2006. [Book chapter]

Perier C, Tieu K, Guegan C, Caspersen C, Jackson-Lewis V, Carelli V, Martinuzzi A, Hirano M, Przedborski S, Vila M. Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage. Proc Natl Acad Sci U S A. 2005. Dec 27;102(52):19126-19131.

Przedborski, S and Tieu, K. Toxic animal models. In: Neurodegenerative Diseases, edited by Beal MF, Lang AE, and Ludolph AC. Cambridge UK: Cambridge University Press, pp. 196-221. 2005. [Book chapter]

Choi DK, Pennathur S, Perier C, Tieu K, Teismann P, Wu DC, Jackson-Lewis V, Vila M, Vonsattel JP, Heinecke JW, Przedborski S. Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson’s disease in mice. J Neurosci. 2005 Jul 13;25(28):6594-6600.

Tieu K, Perier C, Vila M, Caspersen C, Zhang HP, Teismann P, Jackson-Lewis V, Stern DM, Yan SD, Przedborski S. L-3-hydroxyacyl-CoA dehydrogenase II protects in a model of Parkinson’s disease. Ann Neurol. 2004 Jul;56(1):51-60.

Przedborski S., Tieu K., Perier C. and Vila M. MPTP as a mitochondrial neurotoxic model of Parkinson’s disease. Journal of Bioenergetics and Biomembranes. 2004. 36:375-379.

Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, Naini A, Vila M, Jackson-Lewis V, Ramasamy R, Przedborski S. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest. 2003 Sep;112(6):892-901.

Tieu K, Ischiropoulos H, Przedborski S. Nitric oxide and reactive oxygen species in Parkinson’s disease. IUBMB Life. 2003 Jun;55(6):329-335. [Review]

Teismann P, Tieu K, Choi DK, Wu DC, Naini A, Hunot S, Vila M, Jackson-Lewis V, Przedborski S. Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5473-5478.

Wu DC, Teismann P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6145-6150.

Teismann P, Tieu K, Cohen O, Choi DK, Wu du C, Marks D, Vila M, Jackson-Lewis V, Przedborski S. Pathogenic role of glial cells in Parkinson’s disease. Mov Disord. 2003 Feb;18(2):121-129. [Review]

Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, Staal R, Tieu K, Schmitz Y, Yuan CA, Rocha M, Jackson-Lewis V, Hersch S, Sulzer D, Przedborski S, Burke R, Hen R. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14524-14529.

Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, Choi DK, Ischiropoulos H, Przedborski S. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 2002 Mar 1;22(5):1763-1771.