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The Journal of Neuroscience, April 12, 2006, 26(15):4054-4062; doi:10.1523/JNEUROSCI.0603-06.2006

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Neurobiology of Disease
Tubulin-Mediated Binding of Human Immunodeficiency Virus-1 Tat to the Cytoskeleton Causes Proteasomal-Dependent Degradation of Microtubule-Associated Protein 2 and Neuronal Damage

Susanna Aprea, Luis Del Valle, Giuseppe Mameli, Bassel E. Sawaya, Kamel Khalili, and Francesca Peruzzi

Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122

Correspondence should be addressed to Francesca Peruzzi, Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, 1900 12th North Street, Philadelphia, PA 19122. Email: fperuzzi{at}temple.edu

One of the hallmarks of human immunodeficiency virus (HIV)-1 associated pathology in the CNS is deterioration of neuronal processes. Although there is mounting evidence of neuronal toxicity and cell death induced by the HIV-1 transactivating factor Tat, the molecular events linked directly to its detrimental effect on neuronal cells remain unclear. In this study, we used rat embryonic cortical neurons and demonstrated that Tat causes rapid degradation of microtubule-associated protein 2 (MAP2) and the collapse of cytoskeletal filaments. The mechanism of Tat action on MAP2 stability involved Tat-mediated translocation of the proteasome to the site of microtubule filaments. Immunohistochemical analysis of clinical samples from patients with HIV encephalopathy further revealed a significant decrease in MAP2 with predominant cytoplasmic 20S in cortical neurons near microglial nodules. These findings indicate a novel mechanism for the action of Tat on neuronal cells. It involves proteasome-mediated MAP2 degradation and may account for the loss of MAP2 and neuronal damage observed in the brain of AIDS patients with neurological dysfunctions.

Key words: neuron; proteolysis; degeneration; cytoskeleton; apoptosis; recruitment

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Received Oct. 28, 2005; revised March 6, 2006; accepted March 6, 2006.

Correspondence should be addressed to Francesca Peruzzi, Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, 1900 12th North Street, Philadelphia, PA 19122. Email: fperuzzi{at}temple.edu

This article has been cited by other articles:

				H. J. Kim, K. A. Martemyanov, and S. A. Thayer Human Immunodeficiency Virus Protein Tat Induces Synapse Loss via a Reversible Process That Is Distinct from Cell Death J. Neurosci., November 26, 2008; 28(48): 12604 - 12613. [Abstract] [Full Text] [PDF]

				P. Kalantari, O. F. Harandi, P. A. Hankey, and A. J. Henderson HIV-1 Tat Mediates Degradation of RON Receptor Tyrosine Kinase, a Regulator of Inflammation J. Immunol., July 15, 2008; 181(2): 1548 - 1555. [Abstract] [Full Text] [PDF]

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