Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster
IntroductionNumerous neurodegenerative diseases are associated with neuronal dysfunction caused by increased redox stress, often linked to aberrant production of redox-active molecules such as nitric oxide (NO) or oxygen free radicals. One such protein affected by redox-mediated changes is the glyco...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-02-01
|
| Series: | Frontiers in Synaptic Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnsyn.2023.1124061/full |
| _version_ | 1797893770861084672 |
|---|---|
| author | Aelfwin Stone Oliver Cujic Angel Rowlett Sophia Aderhold Emma Savage Bruce Graham Joern R. Steinert |
| author_facet | Aelfwin Stone Oliver Cujic Angel Rowlett Sophia Aderhold Emma Savage Bruce Graham Joern R. Steinert |
| author_sort | Aelfwin Stone |
| collection | DOAJ |
| description | IntroductionNumerous neurodegenerative diseases are associated with neuronal dysfunction caused by increased redox stress, often linked to aberrant production of redox-active molecules such as nitric oxide (NO) or oxygen free radicals. One such protein affected by redox-mediated changes is the glycolytic enzyme triose-phosphate isomerase (TPI), which has been shown to undergo 3-nitrotyrosination (a NO-mediated post-translational modification) rendering it inactive. The resulting neuronal changes caused by this modification are not well understood. However, associated glycation-induced cytotoxicity has been reported, thus potentially causing neuronal and synaptic dysfunction via compromising synaptic vesicle recycling.MethodsThis work uses Drosophila melanogaster to identify the impacts of altered TPI activity on neuronal physiology, linking aberrant TPI function and redox stress to neuronal defects. We used Drosophila mutants expressing a missense allele of the TPI protein, M81T, identified in a previous screen and resulting in an inactive mutant of the TPI protein (TPIM81T, wstd1). We assessed synaptic physiology at the glutamatergic Drosophila neuromuscular junction (NMJ), synapse morphology and behavioural phenotypes, as well as impacts on longevity.ResultsElectrophysiological recordings of evoked and spontaneous excitatory junctional currents, alongside high frequency train stimulations and recovery protocols, were applied to investigate synaptic depletion and subsequent recovery. Single synaptic currents were unaltered in the presence of the wstd1 mutation, but frequencies of spontaneous events were reduced. Wstd1 larvae also showed enhanced vesicle depletion rates at higher frequency stimulation, and subsequent recovery times for evoked synaptic responses were prolonged. A computational model showed that TPI mutant larvae exhibited a significant decline in activity-dependent vesicle recycling, which manifests itself as increased recovery times for the readily-releasable vesicle pool. Confocal images of NMJs showed no morphological or developmental differences between wild-type and wstd1 but TPI mutants exhibited learning impairments as assessed by olfactory associative learning assays.DiscussionOur data suggests that the wstd1 phenotype is partially due to altered vesicle dynamics, involving a reduced vesicle pool replenishment, and altered endo/exocytosis processes. This may result in learning and memory impairments and neuronal dysfunction potentially also presenting a contributing factor to other reported neuronal phenotypes. |
| first_indexed | 2024-04-10T06:58:10Z |
| format | Article |
| id | doaj.art-51c005a7a45d43ba8aadd3eb06271b38 |
| institution | Directory Open Access Journal |
| issn | 1663-3563 |
| language | English |
| last_indexed | 2024-04-10T06:58:10Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Synaptic Neuroscience |
| spelling | doaj.art-51c005a7a45d43ba8aadd3eb06271b382023-02-28T05:53:58ZengFrontiers Media S.A.Frontiers in Synaptic Neuroscience1663-35632023-02-011510.3389/fnsyn.2023.11240611124061Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogasterAelfwin Stone0Oliver Cujic1Angel Rowlett2Sophia Aderhold3Emma Savage4Bruce Graham5Joern R. Steinert6Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United KingdomDivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United KingdomDivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United KingdomDivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United KingdomDivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United KingdomDivision of Computing Science and Mathematics, Faculty of Natural Sciences, University of Stirling, Stirling, United KingdomDivision of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United KingdomIntroductionNumerous neurodegenerative diseases are associated with neuronal dysfunction caused by increased redox stress, often linked to aberrant production of redox-active molecules such as nitric oxide (NO) or oxygen free radicals. One such protein affected by redox-mediated changes is the glycolytic enzyme triose-phosphate isomerase (TPI), which has been shown to undergo 3-nitrotyrosination (a NO-mediated post-translational modification) rendering it inactive. The resulting neuronal changes caused by this modification are not well understood. However, associated glycation-induced cytotoxicity has been reported, thus potentially causing neuronal and synaptic dysfunction via compromising synaptic vesicle recycling.MethodsThis work uses Drosophila melanogaster to identify the impacts of altered TPI activity on neuronal physiology, linking aberrant TPI function and redox stress to neuronal defects. We used Drosophila mutants expressing a missense allele of the TPI protein, M81T, identified in a previous screen and resulting in an inactive mutant of the TPI protein (TPIM81T, wstd1). We assessed synaptic physiology at the glutamatergic Drosophila neuromuscular junction (NMJ), synapse morphology and behavioural phenotypes, as well as impacts on longevity.ResultsElectrophysiological recordings of evoked and spontaneous excitatory junctional currents, alongside high frequency train stimulations and recovery protocols, were applied to investigate synaptic depletion and subsequent recovery. Single synaptic currents were unaltered in the presence of the wstd1 mutation, but frequencies of spontaneous events were reduced. Wstd1 larvae also showed enhanced vesicle depletion rates at higher frequency stimulation, and subsequent recovery times for evoked synaptic responses were prolonged. A computational model showed that TPI mutant larvae exhibited a significant decline in activity-dependent vesicle recycling, which manifests itself as increased recovery times for the readily-releasable vesicle pool. Confocal images of NMJs showed no morphological or developmental differences between wild-type and wstd1 but TPI mutants exhibited learning impairments as assessed by olfactory associative learning assays.DiscussionOur data suggests that the wstd1 phenotype is partially due to altered vesicle dynamics, involving a reduced vesicle pool replenishment, and altered endo/exocytosis processes. This may result in learning and memory impairments and neuronal dysfunction potentially also presenting a contributing factor to other reported neuronal phenotypes.https://www.frontiersin.org/articles/10.3389/fnsyn.2023.1124061/fulltriose-phosphate isomeraseglycationneurodegenerationsynaptic releasevesicle poolneuromuscular junction |
| spellingShingle | Aelfwin Stone Oliver Cujic Angel Rowlett Sophia Aderhold Emma Savage Bruce Graham Joern R. Steinert Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster Frontiers in Synaptic Neuroscience triose-phosphate isomerase glycation neurodegeneration synaptic release vesicle pool neuromuscular junction |
| title | Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster |
| title_full | Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster |
| title_fullStr | Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster |
| title_full_unstemmed | Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster |
| title_short | Triose-phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in Drosophila melanogaster |
| title_sort | triose phosphate isomerase deficiency is associated with a dysregulation of synaptic vesicle recycling in drosophila melanogaster |
| topic | triose-phosphate isomerase glycation neurodegeneration synaptic release vesicle pool neuromuscular junction |
| url | https://www.frontiersin.org/articles/10.3389/fnsyn.2023.1124061/full |
| work_keys_str_mv | AT aelfwinstone triosephosphateisomerasedeficiencyisassociatedwithadysregulationofsynapticvesiclerecyclingindrosophilamelanogaster AT olivercujic triosephosphateisomerasedeficiencyisassociatedwithadysregulationofsynapticvesiclerecyclingindrosophilamelanogaster AT angelrowlett triosephosphateisomerasedeficiencyisassociatedwithadysregulationofsynapticvesiclerecyclingindrosophilamelanogaster AT sophiaaderhold triosephosphateisomerasedeficiencyisassociatedwithadysregulationofsynapticvesiclerecyclingindrosophilamelanogaster AT emmasavage triosephosphateisomerasedeficiencyisassociatedwithadysregulationofsynapticvesiclerecyclingindrosophilamelanogaster AT brucegraham triosephosphateisomerasedeficiencyisassociatedwithadysregulationofsynapticvesiclerecyclingindrosophilamelanogaster AT joernrsteinert triosephosphateisomerasedeficiencyisassociatedwithadysregulationofsynapticvesiclerecyclingindrosophilamelanogaster |