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Pathogenic mechanisms
B13 axonal transport, energy supply and huntingtin
  1. D Zala1,2,3,
  2. V Hinckelmann1,2,3,
  3. G Liot1,2,3,
  4. P Pla1,2,3,
  5. S Humbert1,2,3,
  6. F Saudou1,2,3
  1. 1Institut Curie, Centre Universitaire Paris-Sud, Orsay, France
  2. 2INSERM U1005, Centre Universitaire Paris-Sud, Orsay, France
  3. 3CNRS UMR3306, Centre Universitaire Paris-Sud, Orsay, France

Abstract

Background The mechanisms by which huntingtin induces dysfunction and death of neurons in the brain are not clearly understood but they involve in part the loss of the protective properties of wild-type huntingtin. We demonstrated that huntingtin function is crucial for pathogenesis as huntingtin controls the microtubule-based transport of neurotrophic factors such as BDNF. This function is altered in disease, leading to a decrease in neurotrophic support and death of striatal neurons. Interestingly, the defect in transport might not be restricted to axons but could also involve defects in the retrograde transport of TrkB in striatal dendrites. In HD there is an alteration in energy levels that could result from defects in mitochondria function as well as in the glycolytic machinery. Since fast axonal transport requires consistent energy support over long distances to fuel the molecular motors that transport vesicles, we studied the source of energy for fast axonal transport.

Results We demonstrate that glycolysis, but not mitochondria, provides ATP for the fast axonal transport of vesicles. Inhibiting the mitochondrial ATP synthase or clustering mitochondria in the soma of neurons effectively reduced ATP:ADP ratio within axons, but did not affect vesicle motility. In contrast, pharmacological or genetic inhibition of the glycolytic enzyme, GAPDH, blocked vesicular transport in cultured neurons and in Drosophila larvae. We found that GAPDH localise on vesicles and is transported on vesicles within axons. We found that huntingtin scaffolds GAPDH on vesicles and that vesicular GAPDH is necessary and sufficient to propel vesicles in GAPDH deficient neurons. Together, these findings demonstrate a crucial role for huntingtin in providing energy for axonal transport. Moreover, huntingtin by specifically localising glycolytic machinery on vesicles may supply constant energy, independent of mitochondria, for the processive movement of vesicles over long distances in axons.

  • Axonal transport
  • BDNF
  • glycolysis
  • mitochondria
  • energy

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