Neuron-specific knockdown of solute carrier protein SLC25A46a induces locomotive defects, an abnormal neuron terminal morphology, learning disability, and shortened lifespan
| Autor: | Ryosuke Kowada, Saheb Ali, Kojiro Suda, Ibuki Ueoka, Hideki Yoshida, Masamitsu Yamaguchi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Neuromuscular junction Biology Mitochondrion Article lcsh:RC321-571 03 medical and health sciences 0302 clinical medicine medicine Learning abilities Gene lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Gene knockdown General Neuroscience Neurodegeneration fungi dSLC25A46 medicine.disease Phenotype Solute carrier family Cell biology Mitochondria 030104 developmental biology medicine.anatomical_structure nervous system Drosophila Neuron 030217 neurology & neurosurgery |
| Zdroj: | IBRO Reports, Vol 8, Iss, Pp 65-75 (2020) IBRO Reports |
| ISSN: | 2451-8301 |
| Popis: | Highlights • Neuron-specific dSLC25A46a knockdown resulted in reduced mobility in larvae as well as adults. • Neuron-specific dSLC25A46a knockdown induced an aberrant morphology for NMJ and learning disability. • Neuron-specific dSLC25A46a knockdown induced mitochondrial hyperfusion, the accumulation of ROS and reductions in ATP. Various mutations in the SLC25A46 gene have been reported in mitochondrial diseases that are sometimes classified as type 2 Charcot-Marie-Tooth disease, optic atrophy, and Leigh syndrome. Although human SLC25A46 is a well-known transporter that acts through the mitochondrial outer membrane, the relationship between neurodegeneration in these diseases and the loss-of-function of SLC25A46 remains unclear. Two Drosophila genes, CG8931 (dSLC25A46a) and CG5755 (dSLC25A46b) have been identified as candidate homologs of human SLC25A46. We previously characterized the phenotypes of pan-neuron-specific dSLC25A46b knockdown flies. In the present study, we developed pan-neuron-specific dSLC25A46a knockdown flies and examined their phenotypes. Neuron-specific dSLC25A46a knockdown resulted in reduced mobility in larvae as well as adults. An aberrant morphology for neuromuscular junctions (NMJs), such as a reduced synaptic branch length and decreased number and size of boutons, was observed in dSLC25A46a knockdown flies. Learning ability was also reduced in the larvae of knockdown flies. In dSLC25A46a knockdown flies, mitochondrial hyperfusion was detected in NMJ synapses together with the accumulation of reactive oxygen species and reductions in ATP. These phenotypes were very similar to those of dSLC25A46b knockdown flies, suggesting that dSLC25A46a and dSLC25A46b do not have redundant roles in neurons. Collectively, these results show that the depletion of SLC25A46a leads to mitochondrial defects followed by an aberrant synaptic morphology, resulting in locomotive defects and learning disability. Thus, the dSLC25A46a knockdown fly summarizes most of the phenotypes in patients with mitochondrial diseases, offering a useful tool for studying these diseases. |
| Databáze: | OpenAIRE |
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