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

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

doi:10.1038/s41598-018-23155-2

Philippine C Geiszler, Marie-Christine Pardon + Show 7 more

Open Access

https://doi.org/10.1038/s41598-018-23155-2

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Abstract

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.

Highlights

Neurodegenerative diseases such as Alzheimer’s disease (AD) are complex and the underlying mechanisms involved unclear
The ubiquitin proteasome system (UPS); the major pathway for the degradation of damaged, misfolded and aggregation-prone proteins, has been linked to neurodegenerative disease since ubiquitin was found in their characteristic protein aggregates[4,5,6,7,8]
N-acetyl aspartate (NAA) as one of the most prominent metabolites in 1H magnetic resonance spectroscopy (MRS) of the brain is employed as a general indicator of neuronal health, and mitochondrial function[27,28,29,30,31]

Summary

Introduction

Neurodegenerative diseases such as Alzheimer’s disease (AD) are complex and the underlying mechanisms involved unclear. The other major protein quality control pathway in the cell, was linked to neurodegenerative disease following the observation that loss of autophagy in mouse neurons causes accumulation of ubiquitin-positive aggregates and neurodegeneration, a recent study suggests ubiquitinated proteins are not major targets for basal autophagy[12,13]. Using 400 mHz nuclear magnetic resonance (NMR) spectroscopy we have carried out a temporal region-specific characterisation of the metabolome of neuron-specific 26S proteasome knockout mice (Psmc1fl/fl; CaMKIIα-Cre) between 2 and 6 weeks-old accompanying progressive neurodegeneration and Lewy-like inclusion formation in the forebrain. We have combined our NMR spectroscopy analysis with quantitative histopathological and molecular investigations of activated astrocytes and microglia in Psmc1fl/fl;CaMKIIα-Cre mouse forebrain to inform on putative metabolite changes that may track gliosis

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