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The study of vesicular glycolysis in health and Huntington’s disease

on the February 4, 2021

Doctoral thesis defense of Maximilian MC CLUSKEY

Thursday 4th February at 2 p.m., Maximilian MC CLUSKEY will defend his thesis called "The study of vesicular glycolysis in health and Huntington’s disease".

This thesis was supervised by Frédéric Saudou and Anne-Sophie Nicot.

Abstract :

The axon enables long distance travel of electrical and chemical information between neurons, a process at the basis of neuronal communication and brain function. This information is transported in part by vesicles. Membrane-bound molecular motors propel these vesicles along the axon’s cytoskeleton by consuming ATP. The lab has shown previously that the ATP required for this transport is produced by on-board glycolytic enzymes, thus creating an energetically autonomous microenvironment for vesicular transport. What is more, the transport of BDNF is significantly reduced in Huntington’s disease (HD), a genetic disease caused by an abnormal CAG repeat expansion in the huntingtin (HTT) gene. This leads to insufficient trophic support of BDNF to the striatum where it plays a crucial role in cell survival. HTT is known to scaffold and mediate molecular motors on vesicles. The objectives of this PhD project were therefore to, design an approach to measure glycolytic activity on vesicles in order to understand the intricacies of glycolytic activity on vesicles as well as to identify the link between vesicular glycolysis and insufficient transport in HD.

To do so, we first wanted to describe the differences in metabolic rates and efficiency between cytosolic and vesicular glycolysis. To measure glycolytic activity, we decided to split the pathway into two segments: the first was determined through the NADH production, the product of GAPDH; and the second segment was measured through the ATP production, produced by PGK and PK. Through these measurements, we found that vesicular glycolysis has a greater affinity for its substrates than the cytosol, making the vesicle more efficient at producing NADH and ATP than cytosolic equivalents.

This then led us to question the importance of NAD+ recycling on vesicles. Here we showed, through immunofluorescence and western blot, that LDH, the enzyme responsible for converting pyruvate into lactate and oxidizing NADH in the process, is a vesicle-bound enzyme. Furthermore, we demonstrated that this LDH-dependent NAD+ recycling is crucial for overall glycolytic activity on vesicles and required for BDNF transport in cultured cortical neurons. Hence, axonal vesicles produce ATP via aerobic glycolysis, similarly to the Warburg effect in certain cancer cells.

Finally, we studied the link between vesicular glycolysis and BDNF transport in HD. We showed that HTT interacts more strongly on vesicles with at least two glycolytic enzymes, GAPDH and PFK, and that glycolytic enzyme quantity and activity on vesicles is affected in HD. Based on these results we used previously described TM-GAPDH to artificially stimulate glycolysis specifically on vesicles to demonstrate that this approach was sufficient to restore transport in vitro. This provides evidence of the importance of vesicular glycolysis in BDNF transport and HD pathogenesis.

Jury :

  • Rapporteurs: Carine Pourié and Frédéric Darios
  • Examinateurs: Isabelle Arnal and Hervé Ducouchaud

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Updated on February 1, 2021

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