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Updated: Jan 27, 2026
Simultaneous Imaging of Microglial Dynamics and Neuronal Activity in Awake Mice
Published on: August 23, 2022
Dysregulation of Microglial Function Contributes to Neuronal Impairment in Mcoln1a-Deficient Zebrafish
Wan Jin1, Yimei Dai1, Funing Li2
1Division of Life Science, State Key Laboratory of Molecular Neuroscience and Center of Systems Biology and Human Health, the Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR. China.
Abstract:
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.
Insights
Type IV mucolipidosis (ML-IV) is a neurodegenerative disorder. Zebrafish mcoln1a mutants reveal impaired microglial function contributes to neuronal defects in ML-IV disease.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Type IV mucolipidosis (ML-IV) is a neurodegenerative lysosome storage disorder linked to MCOLN1 gene mutations.
- The precise cellular and molecular mechanisms driving ML-IV's neuronal phenotypes are not fully understood.
Purpose of the Study:
- To investigate the cellular and molecular underpinnings of ML-IV neuronal phenotypes.
- To identify genetic factors contributing to ML-IV pathogenesis using zebrafish models.
Main Methods:
- Forward genetic screening in zebrafish to identify mutants with ML-IV-like phenotypes.
- Characterization of a hypomorphic mcoln1a mutant (biluo).
- Analysis of endosome-lysosome trafficking and neuronal activity in mcoln1a-deficient zebrafish.
Main Results:
- The zebrafish mcoln1a mutant exhibits enlarged late endosomes in microglia, indicative of impaired fusion with lysosomes.
- Aberrant neuronal activity was observed in optic tectal neurons of mcoln1a-deficient mutants.
- Restoring Mcoln1a function in microglia partially rescued the observed neuronal activity defects.
Conclusions:
- Dysregulation of microglial function, specifically impaired endosome-lysosome fusion, contributes to ML-IV pathogenesis.
- Microglia play a significant role in the neurodegenerative processes associated with ML-IV disease.
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