HIV glycoprotein Gp120 impairs fast axonal transport by activating Tak1 signaling pathways
Morfini, Gerardo A.
Brady, Scott T.
MetadataShow full item record
KeywordAxonal transport; Distal sensory polyneuropathy; Gp120; HIV; Mitogen-activated protein kinase; Kinesin
Sensory neuropathies are the most common neurological complication of HIV. Of these, distal sensory polyneuropathy (DSP) is directly caused by HIV infection and characterized by length-dependent axonal degeneration of dorsal root ganglion (DRG) neurons. Mechanisms for axonal degeneration in DSP remain unclear, but recent experiments revealed that the HIV glycoprotein gp120 is internalized and localized within axons of DRG neurons. Based on these findings, we investigated whether intra-axonal gp120 might impair fast axonal transport (FAT), a cellular process critical for appropriate maintenance of the axonal compartment. Significantly, we found that gp120 severely impaired both anterograde and retrograde FAT. Providing a mechanistic basis for these effects, pharmacological experiments revealed an involvement of various phosphotransferases in this toxic effect, including members of mitogen-activated protein kinase pathways (Tak-1, p38, and c-Jun N-terminal Kinase (JNK)), inhibitor of kappa-B-kinase 2 (IKK2), and PP1. Biochemical experiments and axonal outgrowth assays in cell lines and primary cultures extended these findings. Impairments in neurite outgrowth in DRG neurons by gp120 were rescued using a Tak-1 inhibitor, implicating a Tak-1 mitogen-activated protein kinase pathway in gp120 neurotoxicity. Taken together, these observations indicate that kinase-based impairments in FAT represent a novel mechanism underlying gp120 neurotoxicity consistent with the dying-back degeneration seen in DSP. Targeting gp120-based impairments in FAT with specific kinase inhibitors might provide a novel therapeutic strategy to prevent axonal degeneration in DSP.
© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in ASN Neuro 8 (2016): 10.1177/1759091416679073, doi:10.1177/1759091416679073.
Suggested CitationASN Neuro 8 (2016): 10.1177/1759091416679073
The following license files are associated with this item:
Showing items related by title, author, creator and subject.
Elevated levels of diesel range organic compounds in groundwater near Marcellus gas operations are derived from surface activities Drollette, Brian D.; Hoelzer, Kathrin; Warner, Nathaniel R.; Darrah, Thomas H.; Karatum, Osman; O’Connor, Megan P.; Nelson, Robert K.; Fernandez, Loretta A.; Reddy, Christopher M.; Vengosh, Avner; Jackson, Robert B.; Elsner, Martin; Plata, Desiree L. (2015-08)Hundreds of organic chemicals are utilized during natural gas extraction via high volume hydraulic fracturing (HVHF). However, it is unclear if these chemicals, injected into deep shale horizons, reach shallow groundwater ...
Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin Morfini, Gerardo A.; You, Yi-Mei; Pollema, Sarah L.; Kaminska, Agnieszka; Liu, Katherine; Yoshioka, Katsuji; Bjorkblom, Benny; Coffey, Eleanor T.; Bagnato, Carolina; Han, David; Huang, Chun-Fang; Banker, Gary; Pigino, Gustavo F.; Brady, Scott T. (2009-04-28)Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal ...
A novel lipid binding protein is a factor required for MgATP stimulation of the squid nerve Na+/Ca2+ exchanger Berberian, Graciela; Bollo, Mariana; Montich, Guillermo; Roberts, Gretel; DeGiorgis, Joseph A.; DiPolo, Reinaldo; Beauge, Luis (2008-11-14)Here we identify a cytosolic factor essential for MgATP up-regulation of the squid nerve Na+/Ca2+ exchanger. Mass spectroscopy and Western blot analysis established that this factor is a member of the lipocalin super ...