Dissertation Defense: Erin Wenzel
Candidate Name: Erin Wenzel
Advisor: Italo Mocchetti, Ph.D.
Title: Mechanisms of HIV-1 gp120 Neurotoxicity: The Role of Microtubules
Despite the introduction of antiretroviral therapy in 1996, about 50% of HIV-positive individuals demonstrate cognitive impairments known as HIV-associated neurocognitive disorders (HAND). Although neurons cannot be infected by HIV, they show neurite simplification. These morphological alterations are seen in patients with HAND and are recapitulated by HIV envelope protein gp120 in experimental settings. Gp120 binds to chemokine receptors, CXCR4 or CCR5, and initiates neurotoxic signaling cascades. In addition to initiating signaling, gp120 also accumulates within neurons; protein accumulation is a pathological feature in several neurodegenerative disorders.
We have shown that the internalization of gp120 is receptor mediated and dynamin dependent. To establish whether intracellular gp120 is neurotoxic, we used gp120-loaded mesoporous silica nanoparticles. These nanoparticles enter neurons via receptor-independent phagocytosis which allowed us to measure the neurotoxicity of intracellular gp120 alone, without influence from its role in initiating neurotoxic signaling. We found that internalized gp120 is neurotoxic in the absence of chemokine signaling. The data indicate that gp120 binding to chemokine receptors is essential for its internalization. However, subsequent signaling is not the only mechanism through which gp120 is neurotoxic. We hypothesized that internalized gp120 has an autonomous mechanism of neurotoxicity.
Previously, we demonstrated that intracellular gp120 binds to tubulin within neuronal microtubules. Proper structure and function of microtubules is essential for neuronal survival and is regulated by post-translational modifications, including acetylation. Deacetylation of tubulin will eventually result in neuronal injury. We discovered that neurons exposed to gp120 demonstrate deacetylation of tubulin though an increase in histone deacetylase-6 (HDAC6). Deacetylation of tubulin also decreases the association between motor proteins and tubulin resulting in impaired axonal transport of cargo including vesicular brain-derived neurotrophic factor (BDNF). We established that gp120 reduces the velocity of BDNF undergoing bidirectional axonal transport which will eventually lead to aberrant subcellular distribution and impaired release. However, we discovered that HDAC6 inhibition restored the velocity of BDNF to baseline. Inhibition of HDAC6 also compensated for gp120-associated deacetylation and prevented gp120-mediated neuronal injury.
This work establishes a novel neurotoxic mechanism for intracellular gp120 involving alterations to microtubules and identifies a potential neuroprotective therapy to prevent these effects.
Wednesday, May 29 at 12:00pm to 2:00pm
Medical and Dental Building, SW 107
3900 Reservoir Road, N.W., Washington