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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Characterization and chemoproteomic profiling of protein O-GlcNAcylation in SOD1-G93A mouse model
Yi Hao1, Zhongzhong Li2, Xinyan Du2
1National Glycoengineering Research Center, Shandong University, Qingdao, Shandong, China.
Background:
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been found to affect the processing of several important proteins implicated in ALS. However, the overall level and cellular localization of O-GlcNAc during ALS progression are incompletely understood, and large-scale profiling of O-GlcNAcylation sites in this context remains unexplored.
Methods:
By using immunostaining analysis and chemoenzymatic labeling-based quantitative chemoproteomics, we assayed O-GlcNAcylation dynamics of lumbar spinal cords from SOD-G93A mice and their non-transgenic (NTG) littermates, the most widely used animal model for studying ALS pathogenesis.
Results:
We discovered that the global O-GlcNAcylation was significantly reduced at the disease end stage. Correlatively, a great increase of OGA was observed. Immunohistochemistry and immunofluorescence analysis showed a higher proportion of O-GlcNAc-positive neurons in the NTG group, while O-GlcNAc colocalization with astrocytes/microglia was elevated in SOD1-G93A mice. Moreover, we reported the identification of 568 high-confidence O-GlcNAc sites from end-stage SOD1-G93A and NTG mice. Of the 568 sites, 226-many of which occurred on neuronal function and structure-related proteins-were found to be dynamically regulated.
Conclusion:
These data provide a valuable resource for dissecting the functional role of O-GlcNAcylation in ALS and shed light on promising therapeutic avenues for ALS. The chemoenzymatic labeling-based chemoproteomic approach is applicable for probing O-GlcNAc dynamics in various pathological processes.
Insights
Global O-linked N-acetylglucosamine (O-GlcNAc) modification decreases in amyotrophic lateral sclerosis (ALS). This study profiles O-GlcNAc sites, revealing dynamic changes in neuronal proteins and potential therapeutic targets for ALS.
Area of Science:
- Neuroscience
- Biochemistry
- Proteomics
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons.
- Protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification is implicated in ALS pathogenesis.
- Understanding O-GlcNAc dynamics and site-specific regulation in ALS is crucial but incomplete.
Purpose of the Study:
- To investigate the overall level and cellular localization of O-GlcNAc during ALS progression.
- To perform large-scale profiling of O-GlcNAcylation sites in an ALS mouse model.
Main Methods:
- Utilized immunostaining and chemoenzymatic labeling-based quantitative chemoproteomics.
- Analyzed lumbar spinal cords from SOD-G93A mice (ALS model) and non-transgenic (NTG) littermates.
Main Results:
- Global O-GlcNAcylation was significantly reduced at the end stage of ALS.
- Increased O-GlcNAcase (OGA) and altered O-GlcNAc localization in neurons, astrocytes, and microglia were observed.
- Identified 568 O-GlcNAc sites, with 226 dynamically regulated sites on neuronal proteins.
Conclusions:
- O-GlcNAcylation plays a dynamic role in ALS progression.
- Provides a resource for understanding O-GlcNAc function in ALS and identifying therapeutic targets.
- Demonstrates the utility of chemoenzymatic labeling for studying O-GlcNAc dynamics in disease.
