The Ubiquitin Proteasome System in Neurodegenerative disease

The Ubiquitin Proteasome System in Neurodegenerative disease

By Sinead Kinsella PhD

The Ubiquitin Proteasome System (UPS)

The Ubiquitin Proteasome System (UPS) is a regulatory machinery for protein turnover in the cell (Pickart, 2001), and strict regulation of the balance between protein synthesis and degradation is essential for cellular homeostasis (Gaczynska et al., 2001). The UPS is composed of the ubiquitination system, which governs the labelling of proteins for degradation, and the proteasome, which carries out protein degradation (Jansen et al., 2014). Ubiquitin degradation is a highly regulated process with specific targeting of the protein with ubiquitin molecules prior to degradation by the 26S proteasome, also termed the constitutive proteasome (Baumeister et al., 1998). The proteasome also contains a 19S proteasomal subunit which regulates unfolding of the ubiquitinated protein and guides it to the 26S core for degradation, a process requiring ATP (Smith et al., 2005).

The conversion of the UPS to the Immunoproteasome in the CNS

UPS dysfunction has been demonstrated to occur in several proteinopathies and is proposed to contribute to the accumulation of intracellular misfolded protein aggregates. The increased glial reactivity seen in neuroinflammation, termed reactive gliosis, induces a conformational change in the proteasomal subunit composition and the formation of the immunoproteasome (20i) (Jansen et al., 2014). The immunoproteasome is differentiated from the constitutive proteasome by the conversion of the constitutive catalytic subunits β1, β2 and β5 to the immuno-subunits β1i, β2i and β5i (Akiyama et al., 1994). A decrease in the constitutive proteasome and increase in the immunoproteasome correlates with the inflammatory response mediated by glial cells in neurodegenerative disease (Mendonca et al., 2006, Cheroni et al., 2005).

Figure 1: Conversion of the Ubiquitin Proteasome System to the Immunoproteasome. Upon inflammation of cellular stress the constitutive proteasome converts to the immunoproteasome, characterized by the substitution of the β1, β2 and β5 to the immuno-subunits β1i, β2i and β5. This conformational change leads to dysregulated proteasomal degradation and contributes to the accumulation of protein aggregates observed in neurodegenerative pathologies.

The Immunoproteasome in disease

Impairment of the ubiquitin proteasome system is implicated in neurodegenerative disease, with misfolded proteins forming insoluble inclusions as they co-localize with ubiquitin proteasome subunits (Zheng et al., 2014, Ross and Poirier, 2004), leading to increased levels of neuronal misfolded protein aggregates (Jansen et al., 2014, Cheroni et al., 2005, Mori et al., 1987). Interestingly, examination of the UPS in the CNS overexpressing misfolded proteins identified lower UPS activity in neurons compared with glia, which is proposed to account for the higher levels and lack of clearance of protein aggregates observed in neurons (Jansen et al., 2014, Tydlacka et al., 2008). Intracellular aggregation of mutant SOD1 in microglia has been shown to contribute to ALS disease progression (Henkel et al., 2009, Puttaparthi and Elliott, 2005), with both K48-linked and K63-linked ubiquitin chains associated with SOD1G93A aggregate pathology (Tan et al., 2008).

Additionally, in ALS the accumulation of intracellular SOD1G93A aggregates leads to modifications in proteasomal function in an attempt to be cleared and degraded by the ubiquitin proteasome mediated pathway forming what has been called the ‘’immunoproteasome’’ (Tydlacka et al., 2008, Bence et al., 2001). Initial induction of the immunoproteasome is suggested to be a protective mechanism, however it is reported to be ineffective in the clearance of intracellular mutated protein aggregates and is believed to exacerbate pathogenesis (Puttaparthi and Elliott, 2005). In mutant SOD1-associated ALS, M1 microglia have an increased immunoproteasome and increased pro-inflammatory activation, resulting from both intracellular and extracellular mutant SOD1 stimulation, as extracellular SOD1G93A has been demonstrated to be a ligand for TLR2 and TLR4 (Zhao et al., 2010), and intracellular SOD1G93A aggregates induce the formation of the immunoproteasome (Henkel et al., 2009).

Intracellular aggregates of misfolded proteins induce a chronic self-propagating microglial inflammatory response (Orre et al., 2013). Additionally, mutations in Ubiquilin 2 (Ubqln2) are found in to be linked to ALS pathogenesis (Deng et al., 2011), and are proposed to inhibit the targeting of ubiquitinated proteins to the proteasome (Chang and Monteiro, 2015), enhancing aggregate accumulation. Specific inhibitors of the induced immunoproteasome subunits has been proposed as an effective therapy targeting glial cell activation in neurodegeneration (Miller et al., 2013). Furthermore, studies have found that ubiquitin co-localizes with mutant SOD1 aggregates in ALS (Stieber et al., 2000), and reduced proteasomal activity contributes to the lack of clearance of SOD1G93A (Hoffman et al., 1996). In addition, an atypical form of ubiquitination has been identified in Parkinson’s disease as co-localization of α-synuclein aggregates with ubiquitin induce inclusion formation (Zucchelli et al., 2010).

Targeting the immunoproteasome by alleviating the downregulated neuronal proteasome and upregulated the glial cell proteasome may ameliorate the polarization of microglia to the M1 state, thereby providing an alternative therapeutic strategy towards attenuating the chronic inflammatory response driving disease progression in neurodegeneration.


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6th Nov 2018 Sinead Kinsella, PhD

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