Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy
Autor: | Giuseppa Pennetta, James Brindle, Leeanne McGurk, Nagraj Sambrani, Simona Paro, Mary A. O’Connell, Liam Keegan, Marion C. Hogg, Anzer Khan |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Male
RNA editing Adenosine Deaminase Physiology ATG5 Mutant Plant Science Biology Synaptic Transmission Synaptic vesicle General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Structural Biology Autophagy Animals Drosophila Proteins Microautophagy Neurodegeneration lcsh:QH301-705.5 Ecology Evolution Behavior and Systematics 030304 developmental biology 0303 health sciences Cell Biology TOR ADAR Cell biology Drosophila melanogaster lcsh:Biology (General) Larva Mutation Drosophila General Agricultural and Biological Sciences 030217 neurology & neurosurgery Research Article Developmental Biology Biotechnology Genetic screen |
Zdroj: | Khan, A, Paro, S, McGurk, L, Sambrani, N, Hogg, M C, Brindle, J, Pennetta, G, Keegan, L P & O'Connell, M A 2020, ' Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy ', BMC Biology, vol. 18, no. 1, pp. 15 . https://doi.org/10.1186/s12915-020-0747-0 BMC Biology BMC Biology, Vol 18, Iss 1, Pp 1-16 (2020) |
Popis: | BackgroundIn fly brains, theDrosophilaAdar (adenosine deaminase acting on RNA) enzyme edits hundreds of transcripts to generate edited isoforms of encoded proteins. Nearly all editing events are absent or less efficient in larvae but increase at metamorphosis; the larger number and higher levels of editing suggest editing is most required when the brain is most complex. This idea is consistent with the fact thatAdarmutations affect the adult brain most dramatically. However, it is unknown whetherDrosophilaAdar RNA editing events mediate some coherent physiological effect. To address this question, we performed a genetic screen for suppressors ofAdarmutant defects.Adar5G1null mutant flies are partially viable, severely locomotion defective, aberrantly accumulate axonal neurotransmitter pre-synaptic vesicles and associated proteins, and develop an age-dependent vacuolar brain neurodegeneration.ResultsA genetic screen revealed suppression of allAdar5G1mutant phenotypes tested by reduced dosage of theTorgene, which encodes a pro-growth kinase that increases translation and reduces autophagy in well-fed conditions. Suppression ofAdar5G1phenotypes by reduced Tor is due to increased autophagy; overexpression ofAtg5, which increases canonical autophagy initiation, reduces aberrant accumulation of synaptic vesicle proteins and suppresses allAdarmutant phenotypes tested. Endosomal microautophagy (eMI) is another Tor-inhibited autophagy pathway involved in synaptic homeostasis inDrosophila. Increased expression of the key eMI protein Hsc70-4 also reduces aberrant accumulation of synaptic vesicle proteins and suppresses allAdar5G1mutant phenotypes tested.ConclusionsThese findings linkDrosophila Adarmutant synaptic and neurotransmission defects to more general cellular defects in autophagy; presumably, edited isoforms of CNS proteins are required for optimum synaptic response capabilities in the brain during the behaviorally complex adult life stage. |
Databáze: | OpenAIRE |
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