Limits...
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

Scheme of the ubiquitin proteasome system. Proteins are targeted for degradation by ubiquitination via E1, E2, and E3 enzymes. The proteasome recognizes and removes the ubiquitination signal, unfolds the protein and finally degrades it.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126450&req=5

Figure 1: Scheme of the ubiquitin proteasome system. Proteins are targeted for degradation by ubiquitination via E1, E2, and E3 enzymes. The proteasome recognizes and removes the ubiquitination signal, unfolds the protein and finally degrades it.

Mentions: The UPS consists of two key components: the ubiquitination system, which selects and targets proteins towards degradation by ubiquitinating them, and the proteasome, a multimeric protein complex that actually performs the degradation. Protein degradation is a tightly regulated process: before a protein is cleaved by the proteasome, an elaborate process of selection and targeting has taken place exerted by the ubiquitin (Ub) system. This system mediates the conjugation of Ub, a small 76-amino-acid-long modifier. Binding of Ub to the target protein takes place in a three-step reaction. First, Ub is linked to an Ub-activating enzyme (E1) in an ATP-dependent manner. Subsequently, the activated Ub is transferred to an E2 conjugating enzyme, followed by attachment of E2 to a specific E3 ubiquitin ligase enzyme that binds the target protein. Lastly, Ub is transferred by the E2 enzyme to the target protein (Figure 1). Ub itself can be ubiquitinated at one of its seven lysine residues, resulting in various polyubiquitin chain types that each has its own specific signal function. Regulation of protein degradation is also mediated by deubiquitinating enzymes (DUBs) that can reverse ubiquitination by removing Ub residues of mono- or polyubiquitinated proteins (Glickman and Ciechanover, 2002; Lilienbaum, 2013).


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

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

Scheme of the ubiquitin proteasome system. Proteins are targeted for degradation by ubiquitination via E1, E2, and E3 enzymes. The proteasome recognizes and removes the ubiquitination signal, unfolds the protein and finally degrades it.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Scheme of the ubiquitin proteasome system. Proteins are targeted for degradation by ubiquitination via E1, E2, and E3 enzymes. The proteasome recognizes and removes the ubiquitination signal, unfolds the protein and finally degrades it.
Mentions: The UPS consists of two key components: the ubiquitination system, which selects and targets proteins towards degradation by ubiquitinating them, and the proteasome, a multimeric protein complex that actually performs the degradation. Protein degradation is a tightly regulated process: before a protein is cleaved by the proteasome, an elaborate process of selection and targeting has taken place exerted by the ubiquitin (Ub) system. This system mediates the conjugation of Ub, a small 76-amino-acid-long modifier. Binding of Ub to the target protein takes place in a three-step reaction. First, Ub is linked to an Ub-activating enzyme (E1) in an ATP-dependent manner. Subsequently, the activated Ub is transferred to an E2 conjugating enzyme, followed by attachment of E2 to a specific E3 ubiquitin ligase enzyme that binds the target protein. Lastly, Ub is transferred by the E2 enzyme to the target protein (Figure 1). Ub itself can be ubiquitinated at one of its seven lysine residues, resulting in various polyubiquitin chain types that each has its own specific signal function. Regulation of protein degradation is also mediated by deubiquitinating enzymes (DUBs) that can reverse ubiquitination by removing Ub residues of mono- or polyubiquitinated proteins (Glickman and Ciechanover, 2002; Lilienbaum, 2013).

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