A mutation in Drosophila Aldolase Causes Temperature-Sensitive Paralysis, Shortened Lifespan, and Neurodegeneration

Abstract

We describe the characterization of m4, an autosomal recessive, temperature-sensitive paralytic mutant in Drosophila that is associated with shortened lifespan and neurodegeneration. Deletion mapping places the mutation in the gene encoding the glycolytic enzyme, Aldolase. The mutant enzyme contains a single amino acid substitution, which results in decreased steady-state levels of Aldolase with a consequent reduction in adenosine triphosphate (ATP) levels. Transgenic-rescue experiments with a genomic construct containing the entire Aldolase gene confirm that paralysis, reduced lifespan, and neurodegeneration all result from the same mutation. Tissue-specific rescue and RNA interference (RNAi) knockdown experiments indicate that Aldolase function (and presumably glycolysis) is important both in neurons and in glia for normal lifespan and neuronal maintenance over time. Impaired glycolysis in neurons can apparently be rescued in part by glycolytically active glia. However, this rescue may depend on the exact physiological state of the neurons and may also vary in different subsets of neurons. Further studies of m4 and related mutants in Drosophila should help elucidate the connections between energy production and utilization in glia and neurons and lead to better understanding of how metabolic defects impair neuronal function and maintenance.

Keywords::

• glia
• glycolysis
• behavioral mutant
• enzymopathy
• neuroprotection

ACKNOWLEDGEMENTS

We thank Robert Kreber for technical assistance, Aki Ikeda for use of his microtome, and members of the Ganetzky laboratory for helpful suggestions. This research was supported by NIH grants T32 AG000213 (D.L.M.), R01 NS015390 and R01 AG033620 (B.G.), and an undergraduate research grant from the Cargill Benevega Fund (C.H.).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.