The ubiquitin proteasome system in glia and its role in neurodegenerative diseases.

Anne H P Jansen,Eric A J Reits,Elly M Hol

doi:10.3389/fnmol.2014.00073

Abstract

The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases.

Highlights

THE UBIQUITIN PROTEASOME SYSTEM Protein homeostasis is essential for proper function of a cell; both protein synthesis and degradation are tightly regulated
The fact that glial activation can already be observed in early presymptomatic stages advocates for an important if not crucial role for glial cells in the initiation of these diseases (Tai et al, 2007; Faideau et al, 2010)
Glial cells express most of the disease-related proteins, and glial www.frontiersin.org aggregates are observed in some of these neurodegenerative diseases albeit with lower frequencies (Bruijn et al, 1997; Shin et al, 2005; Tong et al, 2014)

Summary

Introduction

THE UBIQUITIN PROTEASOME SYSTEM Protein homeostasis is essential for proper function of a cell; both protein synthesis and degradation are tightly regulated. It remains to be examined in more detail whether and how proteasome levels and activity differ between neurons and glia, which would obviously affect the capacity of cells to maintain proper protein homeostasis. Astrocytes and microglia react to the increase of aggregated proteins in the brain and show altered function, thereby contributing to neuronal dysfunction.

Results

Conclusion