(mentions CMT) Researchers reveal mechanism for neuron self-preservation

October 19, 2009

Researchers reveal mechanism for neuron self-preservation

Study shows PIKfyve protects neurons from calcium overload through degradation

of calcium channels

Tsuruta et al. find that a lipid kinase directs a voltage-gated calcium

channel's degradation to save neurons from a lethal dose of overexcitement. The

study appears in the October 19, 2009 issue of the Journal of Cell Biology

An important player in cellular signaling, calcium is also terribly toxic at

high levels. Neurons have evolved ways to protect themselves against the calcium

influxes that come during periods of intense electrical activity. One way to

limit the calcium flood is to remove the gatekeepers, calcium channels, from the

cell surface. How neurons direct this is clinically important in a range of

disorders, including stroke, Parkinson's disease, and Alzheimer's disease.

In a proteomic screen for binding partners of the CaV1.2 channel, Tsuruta et al.

extracted what seemed a strange companion at first: PIKfyve, the lipid kinase

that generates PI(3,5)P2 and promotes the maturation of endosomes into

lysosomes. Other groups had recently shown that mutations affecting PI(3,5)P2

production cause degeneration of excitable cells in both mice and humans,

including mutants found in ALS and Charcot-Marie-Tooth disease.

The team hypothesized that PIKfyve might be directing CaV1.2 degradation. Using

glutamate excitation to simulate excitotoxic stress, the authors showed that

CaV1.2 is internalized, associates with PIKfyve, and is degraded in the

lysosome. When Tsuruta et al. squelched levels of PIKfyve or PI(3,5)P2, excess

channels stayed at the surface and left neurons vulnerable to apoptosis.

The findings clarify how this neuroprotective mechanism unfolds and suggest that

existing calcium channel–blocking drugs might aid patients with

neurodegenerative disorders stemming from a PI(3,5)P2 defect.

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