Dysregulation of Microglial Function Contributes to Neuronal Impairment in Mcoln1a-Deficient Zebrafish
| Autor: | Lu Zhu, Yimei Dai, Funing Li, Wei Liu, Mingjie Zhang, Jiulin Du, Wenqing Zhang, Zhibin Huang, Wan Jin, Zilong Wen, Jianchao Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
animal structures Endosome 02 engineering and technology Biology Article 03 medical and health sciences Cellular neuroscience Lysosome medicine lcsh:Science Zebrafish Late endosome MCOLN1 Multidisciplinary Model Organism Microglia Mucolipidosis fungi Clinical Neuroscience 021001 nanoscience & nanotechnology medicine.disease biology.organism_classification Cell biology 030104 developmental biology medicine.anatomical_structure nervous system Cellular Neuroscience lcsh:Q 0210 nano-technology Neuroscience |
| Zdroj: | iScience, Vol 13, Iss, Pp 391-401 (2019) iScience |
| ISSN: | 2589-0042 |
| Popis: | Summary Type IV mucolipidosis (ML-IV) is a neurodegenerative lysosome storage disorder caused by mutations in the MCOLN1 gene. However, the cellular and molecular bases underlying the neuronal phenotypes of ML-IV disease remain elusive. Using a forward genetic screening, we identified a zebrafish mutant, biluo, that harbors a hypomorphic mutation in mcoln1a, one of the two zebrafish homologs of mammalian MCOLN1. The mcoln1a-deficient mutants display phenotypes partially recapitulating the key features of ML-IV disorder, including the accumulation of enlarged late endosomes in microglia and aberrant neuronal activities in both spontaneous and visual-evoking conditions in optic tectal neurons. We further show that the accumulation of enlarged late endosomes in microglia is caused by the impairment of late endosome and lysosome fusion and the aberrant neuronal activities can be partially rescued by the reconstitution of Mcoln1a function in microglia. Our findings suggest that dysregulation of microglial function may contribute to the development and progression of ML-IV disease. Graphical Abstract Highlights • mcoln1a-deficient fish display microglia impairment and aberrant neuronal activity • The aberrant neuronal activity can be rescued by expressing WT mcoln1a in microglia • Impairment of microglia-neuron contact contributes to the aberrant neuronal activity Cellular Neuroscience; Clinical Neuroscience; Model Organism; Neuroscience |
| Databáze: | OpenAIRE |
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