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The Journal of Neuroscience, October 22, 2008, 28(43):10825-10834; doi:10.1523/JNEUROSCI.3001-08.2008

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Neurobiology of Disease
Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration

Tamy C. Frank-Cannon,¹ Thi Tran,¹ Kelly A. Ruhn,¹ Terina N. Martinez,¹ John Hong,¹ Marian Marvin,² Meagan Hartley,² Isaac Treviño,¹ Daniel E. O'Brien,¹ Bradford Casey,² Matthew S. Goldberg,^2,3 and Malú G. Tansey¹

Departments of ¹Physiology, ²Neurology, and ³Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040

Correspondence should be addressed to Dr. Malú G. Tansey, Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9040. Email: malu.tansey{at}utsouthwestern.edu

The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient (parkin–/–) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin–/– mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin–/– mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin–/– mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.

Key words: Parkin; neuroinflammation; dopaminergic; nigrostriatal degeneration; tumor necrosis factor; Parkinson's disease

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Received June 23, 2008; revised Aug. 30, 2008; accepted Sept. 10, 2008.

Correspondence should be addressed to Dr. Malú G. Tansey, Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9040. Email: malu.tansey{at}utsouthwestern.edu

This article has been cited by other articles:

				M. P. Burns, L. Zhang, G. W. Rebeck, H. W. Querfurth, and C. E.-H. Moussa Parkin promotes intracellular A{beta}1-42 clearance Hum. Mol. Genet., September 1, 2009; 18(17): 3206 - 3216. [Abstract] [Full Text] [PDF]

				C. Y. Chung, J. B. Koprich, H. Siddiqi, and O. Isacson Dynamic Changes in Presynaptic and Axonal Transport Proteins Combined with Striatal Neuroinflammation Precede Dopaminergic Neuronal Loss in a Rat Model of AAV {alpha}-Synucleinopathy J. Neurosci., March 18, 2009; 29(11): 3365 - 3373. [Abstract] [Full Text] [PDF]

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