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

Jansen AH, Reits EA, Hol EM - Front Mol Neurosci (2014)

Bottom Line: The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins.This process is called reactive gliosis, which in turn affects UPS function in glial cells.During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Histology, Academic Medical Center Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

The role of various glial cells in the healthy and diseased CNS. (A) In the healthy situation, astrocytes support neurons by filtering nutrients from the blood and modulating synapses, oligodendrocytes wrap axons in isolating myelin sheets and microglia scan the environment for dead cells or invading pathogens. (B) During reactive gliosis in neurodegenerative diseases, oligodendrocytes and astrocytes lose their normal support function. Astrocytes decrease glutamate uptake from the synapse, leading to excitotoxicity. Microglia become activated and phagocytize dead cells and start to secrete pro-inflammatory cytokines that activate astrocytes. Both reactive astrocytes and activated microglia upregulate immunoproteasome expression. In particular diseases, demyelination of the axons is observed due to oligodendrocyte dysfunction.
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Figure 2: The role of various glial cells in the healthy and diseased CNS. (A) In the healthy situation, astrocytes support neurons by filtering nutrients from the blood and modulating synapses, oligodendrocytes wrap axons in isolating myelin sheets and microglia scan the environment for dead cells or invading pathogens. (B) During reactive gliosis in neurodegenerative diseases, oligodendrocytes and astrocytes lose their normal support function. Astrocytes decrease glutamate uptake from the synapse, leading to excitotoxicity. Microglia become activated and phagocytize dead cells and start to secrete pro-inflammatory cytokines that activate astrocytes. Both reactive astrocytes and activated microglia upregulate immunoproteasome expression. In particular diseases, demyelination of the axons is observed due to oligodendrocyte dysfunction.

Mentions: Neuroglia were first described by the German pathologist Rudolf Virchow already more than 150 years ago. For a long time these cells were considered as nerve glue, a kind of connective tissue holding the brain together. In contrast to neurons, glia are not electrically excitable. This made it difficult to study these cells, and as a consequence, most neuroscientific research was focused on neuronal function. When sophisticated molecular tools became available which made it possible to study the physiology of glial cells, this has led to a change in the neurocentric view of neuroscientists. During the last decades, it has become evident that glial cells are essential for proper neuronal function, are actively involved in neuronal communication, and form the immune system of the brain. As diverse as different glial cells are in morphology and origin, as diverse they are likely in their function. They take care of the general homeostasis in the brain, insulate neurons, and protect against pathogenic invaders (Kettenmann and Verkhratsky, 2008). The ratio between neurons and glia in the human central nervous system (CNS) is about 1:1, with oligodendrocytes being the most abundant type of glial cells (75.6%), followed by astrocytes (17.3%) and microglia (6.5%) in human male brains (Pelvig et al., 2008). Below, the most important glial cell types and their functions are described (Figure 2).


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

Jansen AH, Reits EA, Hol EM - Front Mol Neurosci (2014)

The role of various glial cells in the healthy and diseased CNS. (A) In the healthy situation, astrocytes support neurons by filtering nutrients from the blood and modulating synapses, oligodendrocytes wrap axons in isolating myelin sheets and microglia scan the environment for dead cells or invading pathogens. (B) During reactive gliosis in neurodegenerative diseases, oligodendrocytes and astrocytes lose their normal support function. Astrocytes decrease glutamate uptake from the synapse, leading to excitotoxicity. Microglia become activated and phagocytize dead cells and start to secrete pro-inflammatory cytokines that activate astrocytes. Both reactive astrocytes and activated microglia upregulate immunoproteasome expression. In particular diseases, demyelination of the axons is observed due to oligodendrocyte dysfunction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126450&req=5

Figure 2: The role of various glial cells in the healthy and diseased CNS. (A) In the healthy situation, astrocytes support neurons by filtering nutrients from the blood and modulating synapses, oligodendrocytes wrap axons in isolating myelin sheets and microglia scan the environment for dead cells or invading pathogens. (B) During reactive gliosis in neurodegenerative diseases, oligodendrocytes and astrocytes lose their normal support function. Astrocytes decrease glutamate uptake from the synapse, leading to excitotoxicity. Microglia become activated and phagocytize dead cells and start to secrete pro-inflammatory cytokines that activate astrocytes. Both reactive astrocytes and activated microglia upregulate immunoproteasome expression. In particular diseases, demyelination of the axons is observed due to oligodendrocyte dysfunction.
Mentions: Neuroglia were first described by the German pathologist Rudolf Virchow already more than 150 years ago. For a long time these cells were considered as nerve glue, a kind of connective tissue holding the brain together. In contrast to neurons, glia are not electrically excitable. This made it difficult to study these cells, and as a consequence, most neuroscientific research was focused on neuronal function. When sophisticated molecular tools became available which made it possible to study the physiology of glial cells, this has led to a change in the neurocentric view of neuroscientists. During the last decades, it has become evident that glial cells are essential for proper neuronal function, are actively involved in neuronal communication, and form the immune system of the brain. As diverse as different glial cells are in morphology and origin, as diverse they are likely in their function. They take care of the general homeostasis in the brain, insulate neurons, and protect against pathogenic invaders (Kettenmann and Verkhratsky, 2008). The ratio between neurons and glia in the human central nervous system (CNS) is about 1:1, with oligodendrocytes being the most abundant type of glial cells (75.6%), followed by astrocytes (17.3%) and microglia (6.5%) in human male brains (Pelvig et al., 2008). Below, the most important glial cell types and their functions are described (Figure 2).

Bottom Line: The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins.This process is called reactive gliosis, which in turn affects UPS function in glial cells.During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Histology, Academic Medical Center Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus