The cost of a giant axon

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Wakoto Matsuda, Takahiro Furuta, Takeshi Kaneko and colleagues (2009); Eleftheria Pissadaki and J. Paul Bolam (Oxford, 2013); Consiglia Pacelli, Louis-Éric Trudeau and colleagues (Université de Montréal, 2015). Funders were not read.

What happened

In 2009 Matsuda's group labelled single nigral neurons in rats (eight neurons reconstructed) and found each one's axon covers on average 2.7% of the striatum's volume (range 0.45–5.7%). In 2013 Pissadaki and Bolam built a computer model of these axons and found that the energy cost of nerve firing rises steeply with arbor size and complexity. For human neurons they estimated over 1 million synapses and over 4 metres of axon per cell. Front Comput Neurosci 7:13. In 2015 Pacelli tested the idea in cultured neurons: nigral neurons had higher baseline mitochondrial output, less spare capacity and far more branching than the more resilient neighbouring ventral tegmental area neurons. Pruning branches with Semaphorin 7A lowered their energy use and made them less vulnerable to the toxins MPP+ and rotenone. The calcium-channel blocker isradipine protected against MPP+ but not rotenone. Current Biology 25:2349–2360, published online August 2015.

Why it moved us toward a cure

It offers a concrete reason for the disease's targeting, linking mitochondrial defects (landmark 11, landmark 15) and the calcium-pacemaking load (landmark 57) into one picture: a cell near its energy limit. That suggests treatments that ease energy demand or boost mitochondrial reserve.

Outcome

Open. The 4 m and 1 million figures are model estimates, not measurements. The idea is supported by one cell study (Pacelli) and a model, and has not been tested in patients. No erratum or retraction is listed in Europe PMC for the three papers. Neuroprotective trials based on energy support have not slowed disease (landmark 70, landmark 26).

Sources

• Pissadaki & Bolam, Front Comput Neurosci 2013;7:13, DOI 10.3389/fncom.2013.00013
• Matsuda et al., J Neurosci 2009;29:444–453, DOI 10.1523/JNEUROSCI.4029-08.2009
• Pacelli et al., Curr Biol 2015;25:2349–2360, DOI 10.1016/j.cub.2015.07.050, PubMed 26320949 (Neuroscience News summary, 28 Aug 2015)
• Not yet verified: full texts; how the human axon-length estimate was derived; whether reducing arbor size or energy load helps in any patient-relevant model.