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A27 Targeting glutamine dehydrogenase activity to induce autophagy and ameliorate neuronal degeneration; studies using a drosophila model for huntington’ disease
  1. Paola Bellosta1,2,
  2. Chiara Paiardi3,
  3. Maria E Pasini3
  1. 1Center for Integrative Biology, University of Trento, Trento-Italy
  2. 2Department of Medicine and Endocrinology, NYU Langone Medical Center, New York, USA
  3. 3University of Milan, Milan, Italy


Background Pathological evidences showed that glutamate might play a role in HD. In the brain glutamate is maintained at physiological level by a non-autonomous cycle between glia and neurons called glutamate-glutamine cycle (GGC).

Aims In order to understand the function of this cycle in neuronal survival and HD, we decide to use the flexibility of the genetic model Drosophila melanogaster to manipulate in neurons the expression of key enzyme of the GGC, such as Glutamine Synthetsae1 (Gs1) that produces glutamine from glutamate, and of Glutamate Dehydrogenase (GDH) the enzyme that converts glutamate to alfa-keto glutarate and viceversa.

Methods and results Using a model for Huntington’s disease, that expresses the mutant huntingtin (HttQ93) in neurons, we show that genetic reduction of GDH ameliorates animal motility. At the cellular level, reducing GDH activity results in a significative reduction of the size of toxic HTT aggregates that correlates with increased autophagy and reduced TOR signaling. Moreover, we show a similar effect of GDH in a model for Amyotrophic Lateral Sclerosis (C9orf72-G4C2), suggesting a common mechanism for GDH to ameliorate neuronal death. Conclusions: In the future we would like to use different animal models (flies, zebrafish, mouse) and human cells to elucidate the mechanisms that connect GDH activity with autophagy in glia and neurons, and to identify using drug design techniques and High Throughput Screens, small molecules capable of interfering with GDH activity as potential therapeutic approach in HD and eventually others proteinopathies.

This project was supported by Fondazione Cariplo 20140703, and EHDN seed funds-698

  • HD
  • Glutamine
  • Glutamate
  • GDH
  • autophagy
  • aggregates
  • Drosophila

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