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Dynamic metabolic patterns tracking neurodegeneration and gliosis following 26S proteasome dysfunction in mouse forebrain neurons

Geiszler, Philippine C.; Ugun-Klusek, Aslihan; Lawler, Karen; Pardon, Marie-Christine; Yuchun, Ding; Bai, Li; Daykin, Clare; Auer, Dorothee P.; Bedford, Lynn


Philippine C. Geiszler

Aslihan Ugun-Klusek

Karen Lawler

Ding Yuchun

Li Bai

Clare Daykin

Lynn Bedford


Metabolite profiling is an important tool that may better capture the multiple features of neurodegeneration. With the considerable parallels between mouse and human metabolism, the use of metabolomics in mouse models with neurodegenerative pathology provides mechanistic insight and ready translation into aspects of human disease. Using 400 MHz nuclear magnetic resonance spectroscopy we have carried out a temporal region-specific investigation of the metabolome of neuron-specific 26S proteasome knockout mice characterised by progressive neurodegeneration and Lewy-like inclusion formation in the forebrain. An early significant decrease in N-acetyl aspartate revealed evidence of neuronal dysfunction before cell death that may be associated with changes in brain neuroenergetics, underpinning the use of this metabolite to track neuronal health. Importantly, we show early and extensive activation of astrocytes and microglia in response to targeted neuronal dysfunction in this context, but only late changes in myo-inositol; the best established glial cell marker in magnetic resonance spectroscopy studies, supporting recent evidence that additional early neuroinflammatory markers are needed. Our results extend the limited understanding of metabolite changes associated with gliosis and provide evidence that changes in glutamate homeostasis and lactate may correlate with astrocyte activation and have biomarker potential for tracking neuroinflammation.


Geiszler, P. C., Ugun-Klusek, A., Lawler, K., Pardon, M., Yuchun, D., Bai, L., …Bedford, L. (in press). Dynamic metabolic patterns tracking neurodegeneration and gliosis following 26S proteasome dysfunction in mouse forebrain neurons. Scientific Reports, 8, Article 4833.

Journal Article Type Article
Acceptance Date Mar 2, 2018
Online Publication Date Mar 19, 2018
Deposit Date Mar 19, 2018
Publicly Available Date Mar 19, 2018
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Article Number 4833
Public URL
Publisher URL


Mouse s41598-018-23155-2.pdf (3.4 Mb)

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