Editors' ChoiceNeurodegeneration

Dousing the Flames to Repair Brains

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Science Translational Medicine  14 Apr 2010:
Vol. 2, Issue 27, pp. 27ec60
DOI: 10.1126/scitranslmed.3001146

Inflammatory neurodegenerative conditions—such as multiple sclerosis, cerebral HIV infection, or stroke—deliver the one-two punch. Not only do these diseases induce nerve cell death, they also block neuron regeneration as a result of the inflammatory environment. With the fairly recent recognition of the potential for neural progenitor cells (NPCs) to replace lost brain tissue, questions have arisen as to whether the inflammatory process central to these illnesses impedes the viability or differentiation of NPCs. Wang and colleagues shed light on this issue in their recent study of activated T cell effects on NPCs.

Using human NPCs cultured from fetal brain specimens of 7 to 8 weeks’ gestation, the researchers found that the serine protease granzyme B, which is released from activated T cells during inflammation, impaired NPC proliferation and neuronal differentiation in culture. In contrast, differentiation of NPCs into a second class of brain cells, astrocytes, was increased under the same conditions. Depletion of granzyme B from the cell cultures with a monoclonal antibody attenuated these effects on NPCs, as did pretreatment with pertussis toxin, suggesting that toxin-sensitive G protein–coupled receptors on NPCs mediate the granzyme B effects. Further, granzyme B exposure spurred expression of a plasma membrane–bound, voltage-dependent potassium channel (called Kv1.3) on NPCs in a dose-dependent manner, and pertussis toxin blocked the activation of channel-encoding gene expression. Lastly, direct inhibition of potassium channel function in vivo significantly attenuated the effects of both activated T cells and granzyme B on NPC proliferation in the dentate gyrus of the rat hippocampus. This work suggests that the inflammatory process itself impedes the restorative function of NPCs and that this mechanism may be at work in the context of neurodegenerative diseases. Characterization of the cellular pathways that mediate this process may unveil new therapeutic targets and forge a fresh route toward neurorestorative therapy.

T. Wang et al., Activated T-cells inhibit neurogenesis by releasing granzyme B: Rescue by Kv1.3 blockers. J. Neurosci. 30, 5020–5027 (2010). [Abstract]

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