Spatially distinct and functionally independent mechanisms of axonal degeneration in a model of HIV-associated sensory neuropathy

Giorgia Melli, Sanjay C. Keswani, Angela Fischer, Weiran Chen, Ahmet Hoke

Research output: Contribution to journalArticle

Abstract

Sensory polyneuropathies are the most frequent neurological complication of human immunodeficiency virus (HIV) infection. Distal symmetric polyneuropathy (DSP), associated with HIV infection, is characterized by length-dependent axonal degeneration of sensory fibres. In rodent dorsal root ganglia (DRG) cultures, HIV viral envelope protein gp120 results in neurotoxicity and axonal degeneration. Since it is unknown whether the axonal degeneration is a consequence of neuronal death or whether it is due to a direct toxic effect on axons, we investigated gp120-induced axonal toxicity using compartmentalized cultures of sensory neurons. Our results show that gp120 causes neuronal apoptosis and axonal degeneration through two, independent and spatially separated mechanisms of action: (i) an indirect insult to cell bodies, requiring the presence of Schwann cells, results in neuronal apoptotic death and subsequent axonal degeneration; (ii) a direct, local toxicity exerted on axons through activation of mitochondrial caspase pathway that is independent of cell body. This local axonal toxicity is mediated through binding of gp120 to axonal chemokine receptors and can be prevented by chemokine receptor blockers. In conclusion, we propose a novel pathway of axonal degeneration mediated by gp120 that is dependent on local activation of caspases in the axon. This observation suggests that axonal protection is a relevant therapeutic target for HIV-associated sensory neuropathy. Furthermore, chemokine receptor inhibitors, which are currently being developed as HIV entry inhibitor drugs, may also have a therapeutic role in HIV-associated peripheral neuropathies by preventing axonal degeneration.

Original languageEnglish (US)
Pages (from-to)1330-1338
Number of pages9
JournalBrain
Volume129
Issue number5
DOIs
StatePublished - May 2006

Fingerprint

HIV
Chemokine Receptors
Axons
Polyneuropathies
Virus Diseases
Caspases
Human Immunodeficiency Virus env Gene Products
Viral Envelope Proteins
Virus Internalization
Poisons
Schwann Cells
Spinal Ganglia
Peripheral Nervous System Diseases
Sensory Receptor Cells
Rodentia
Apoptosis
Therapeutics
Pharmaceutical Preparations
Cell Body

Keywords

  • Apoptosis
  • Axonal degeneration
  • Caspase
  • Chemokine receptor inhibitors
  • gp120
  • HIV-neuropathy

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Spatially distinct and functionally independent mechanisms of axonal degeneration in a model of HIV-associated sensory neuropathy. / Melli, Giorgia; Keswani, Sanjay C.; Fischer, Angela; Chen, Weiran; Hoke, Ahmet.

In: Brain, Vol. 129, No. 5, 05.2006, p. 1330-1338.

Research output: Contribution to journalArticle

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