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Molecular Pathways of Neurodegeneration in Parkinson's Disease
Ted M. Dawson1,2,3* and
Valina L. Dawson1,2,3,4
Parkinson's disease (PD) is a complex disorder with many differentcauses, yet they may intersect in common pathways, raising thepossibility that neuroprotective agents may have broad applicabilityin the treatment of PD. Current evidence suggests that mitochondrialcomplex I inhibition may be the central cause of sporadic PDand that derangements in complex I cause -synuclein aggregation,which contributes to the demise of dopamine neurons. Accumulationand aggregation of -synuclein may further contribute to thedeath of dopamine neurons through impairments in protein handlingand detoxification. Dysfunction of parkin (a ubiquitin E3 ligase)and DJ-1 could contribute to these deficits. Strategies aimedat restoring complex I activity, reducing oxidative stress and-synuclein aggregation, and enhancing protein degradation mayhold particular promise as powerful neuroprotective agents inthe treatment of PD.
1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 3 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 4 Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
* To whom correspondence should be addressed. E-mail: tdawson{at}jhmi.edu
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Intrasarcoplasmic Amyloidosis Impairs Proteolytic Function of Proteasomes in Cardiomyocytes by Compromising Substrate Uptake.
Q. Chen, J.-B. Liu, K. M. Horak, H. Zheng, A. R.K. Kumarapeli, J. Li, F. Li, A. M. Gerdes, E. F. Wawrousek, and X. Wang (2005)
Circ. Res.
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Present and future drug treatment for Parkinson's disease.
The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor.
S Goldwurm, A D. Fonzo, E J Simons, C F Rohe, M Zini, M Canesi, S Tesei, A Zecchinelli, A Antonini, C Mariani, et al. (2005)
J. Med. Genet.
42, e65
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Partial Mitochondrial Inhibition Causes Striatal Dopamine Release Suppression and Medium Spiny Neuron Depolarization via H2O2 Elevation, Not ATP Depletion.
L. Bao, M. V. Avshalumov, and M. E. Rice (2005)
J. Neurosci.
25, 10029-10040
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Wild-type PINK1 Prevents Basal and Induced Neuronal Apoptosis, a Protective Effect Abrogated by Parkinson Disease-related Mutations.
A. Petit, T. Kawarai, E. Paitel, N. Sanjo, M. Maj, M. Scheid, F. Chen, Y. Gu, H. Hasegawa, S. Salehi-Rad, et al. (2005)
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Dieldrin Induces Ubiquitin-Proteasome Dysfunction in {alpha}-Synuclein Overexpressing Dopaminergic Neuronal Cells and Enhances Susceptibility to Apoptotic Cell Death.
F. Sun, V. Anantharam, C. Latchoumycandane, A. Kanthasamy, and A. G. Kanthasamy (2005)
J. Pharmacol. Exp. Ther.
315, 69-79
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Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases.
Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling.
Y. Yang, S. Gehrke, Md. E. Haque, Y. Imai, J. Kosek, L. Yang, M. F. Beal, I. Nishimura, K. Wakamatsu, S. Ito, et al. (2005)
PNAS
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Investigating the Receptor-independent Neuroprotective Mechanisms of Nicotine in Mitochondria.
Y.-X. Xie, E. Bezard, and B.-L. Zhao (2005)
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Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death.
H. S. Ko, R. von Coelln, S. R. Sriram, S. W. Kim, K. K. K. Chung, O. Pletnikova, J. Troncoso, B. Johnson, R. Saffary, E. L. Goh, et al. (2005)
J. Neurosci.
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Tyrosine Phosphorylation Regulates the Proteolytic Activation of Protein Kinase C{delta} in Dopaminergic Neuronal Cells.
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Bcl-x Is Required for Proper Development of the Mouse Substantia Nigra.
J. M. Savitt, S. S. Jang, W. Mu, V. L. Dawson, and T. M. Dawson (2005)
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-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of 
