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Articles, Neurobiology of Disease

Leucine-Rich Repeat Kinase 2 Modulates Neuroinflammation and Neurotoxicity in Models of Human Immunodeficiency Virus 1-Associated Neurocognitive Disorders

Jenna M. Puccini, Daniel F. Marker, Tim Fitzgerald, Justin Barbieri, Christopher S. Kim, Patrick Miller-Rhodes, Shao-Ming Lu, Stephen Dewhurst and Harris A. Gelbard
Journal of Neuroscience 1 April 2015, 35 (13) 5271-5283; https://doi.org/10.1523/JNEUROSCI.0650-14.2015
Jenna M. Puccini
1Center for Neural Development and Disease and
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Daniel F. Marker
1Center for Neural Development and Disease and
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Tim Fitzgerald
3Graduate Program in Medical Illustration, Rochester Institute of Technology, Rochester, New York 14623
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Justin Barbieri
1Center for Neural Development and Disease and
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Christopher S. Kim
1Center for Neural Development and Disease and
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Patrick Miller-Rhodes
1Center for Neural Development and Disease and
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Shao-Ming Lu
1Center for Neural Development and Disease and
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Stephen Dewhurst
2Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642, and
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Harris A. Gelbard
1Center for Neural Development and Disease and
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Abstract

Leucine-rich repeat kinase 2 (LRRK2) is the single most common genetic cause of both familial and sporadic Parkinson's disease (PD), both of which share pathogenetic and neurologic similarities with human immunodeficiency virus 1 (HIV-1)-associated neurocognitive disorders (HAND). Pathologic LRRK2 activity may also contribute to neuroinflammation, because microglia lacking LRRK2 exposed to proinflammatory stimuli have attenuated responses. Because microglial activation is a hallmark of HIV-1 neuropathology, we have investigated the role of LRRK2 activation using in vitro and in vivo models of HAND. We hypothesize that LRRK2 is a key modulator of microglial inflammatory responses, which play a pathogenic role in both HAND and PD, and that these responses may cause or exacerbate neuronal damage in these diseases. The HIV-1 Tat protein is a potent neurotoxin produced during HAND that induces activation of primary microglia in culture and long-lasting neuroinflammation and neurotoxicity when injected into the CNS of mice. We found that LRRK2 inhibition attenuates Tat-induced pS935–LRRK2 expression, proinflammatory cytokine and chemokine expression, and phosphorylated p38 and Jun N-terminal kinase signaling in primary microglia. In our murine model, cortical Tat injection in LRRK2 knock-out (KO) mice results in significantly diminished neuronal damage, as assessed by microtubule-associated protein 2 (MAP2), class III β-tubulin TUJ1, synapsin-1, VGluT, and cleaved caspase-3 immunostaining. Furthermore, Tat-injected LRRK2 KO animals have decreased infiltration of peripheral neutrophils, and the morphology of microglia from these mice were similar to that of vehicle-injected controls. We conclude that pathologic activation of LRRK2 regulates a significant component of the neuroinflammation associated with HAND.

  • HIV-1
  • LRRK2
  • microglia
  • neuroinflammation
  • neurotoxicity
  • Parkinson's disease
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The Journal of Neuroscience: 35 (13)
Journal of Neuroscience
Vol. 35, Issue 13
1 Apr 2015
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Leucine-Rich Repeat Kinase 2 Modulates Neuroinflammation and Neurotoxicity in Models of Human Immunodeficiency Virus 1-Associated Neurocognitive Disorders
Jenna M. Puccini, Daniel F. Marker, Tim Fitzgerald, Justin Barbieri, Christopher S. Kim, Patrick Miller-Rhodes, Shao-Ming Lu, Stephen Dewhurst, Harris A. Gelbard
Journal of Neuroscience 1 April 2015, 35 (13) 5271-5283; DOI: 10.1523/JNEUROSCI.0650-14.2015

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Leucine-Rich Repeat Kinase 2 Modulates Neuroinflammation and Neurotoxicity in Models of Human Immunodeficiency Virus 1-Associated Neurocognitive Disorders
Jenna M. Puccini, Daniel F. Marker, Tim Fitzgerald, Justin Barbieri, Christopher S. Kim, Patrick Miller-Rhodes, Shao-Ming Lu, Stephen Dewhurst, Harris A. Gelbard
Journal of Neuroscience 1 April 2015, 35 (13) 5271-5283; DOI: 10.1523/JNEUROSCI.0650-14.2015
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Keywords

  • HIV-1
  • LRRK2
  • microglia
  • neuroinflammation
  • neurotoxicity
  • Parkinson's disease

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