Ubiquitin proteasome system in Parkinson's disease: A keeper or a witness?

Abstract

Objective The aim of this work was to evaluate the role of Ubiquitin-Proteasome System (UPS) on mitochondrial-driven alpha-synuclein (aSN) clearance in in vitro, ex vivo and in vivo Parkinson disease (PD) cellular models. Method We used SH-SY5Y ndufa2 knock-down (KD) cells, PD cybrids and peripheral blood mononuclear cells (PBMC) from patients meeting the diagnostic criteria for PD. We quantified aSN aggregation, proteasome activity and protein ubiquitination levels. In PBMC of PD patients population we evaluated aSN levels in plasma and the influence of several demographic characteristics in the above mentioned determinations. Results We found that ubiquitin-independent proteasome activity was up-regulated in SH-SY5Y ndufa2 KD cells while a down regulation was observed in PD cybrids and PBMC. Moreover, we observed an increase in protein ubiquitination that correlates with a decrease in ubiquitin-dependent proteasome activity. Accordingly, proteasome inhibition prevented ubiquitin-dependent aSN clearance. Ubiquitin-independent proteasome activity was positively correlated with ubiquitination in PBMC. We also report a negative correlation of chymotrypsin-like activity with age in control and late-onset PD groups. Total ubiquitin content is positively correlated with aSN oligomers levels, which leads to an age-dependent increase of aSN ubiquitination in LOPD. Moreover, aSN levels are increased in the plasma of PD patients. Interpretation aSN oligomers are ubiquitinated and we identified an ubiquitin-dependent clearance insufficiency with accumulation of both aSN and ubiquitin. However, SH-SY5Y ndufa2 KD cells showed a significant up-regulation of ubiquitin-independent proteasomal enzymatic activity that could mean a cell rescue attempt. Moreover, we identified that UPS function is age-dependent in PBMC.

Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice

“…Similarly, astrogliosis, S100B positive cell numbers, co-localization within astrocytes, and the HC neurogenesis deficit exceeded the observed pathology in the OB, rendering the hippocampal DG a more susceptible region in regard to α-syn induced pathology. The impact of ubiquitinated α-syn in aggregate formation is yet incompletely defined, but ample evidence suggest, that it directly correlates with a dysfunction of clearance pathways, including the ubiquitin proteasome system (UPS) (Rideout et al, 2001; Snyder et al, 2003; Tofaris et al, 2001) and autophagy (Ebrahimi-Fakhari et al, 2011; Rott et al, 2011) but also mitochondrial pathology and an increase of α-syn oligomers (Martins-Branco et al, 2012). Previous studies reported that the A30P mutation per se fortifies dysfunction of UPS (Petrucelli et al, 2002), impairs chaperone-mediated autophagy (Cuervo et al, 2004) and its oligomerization process (Conway et al, 1998; Li et al, 2002; Narhi et al, 1999) further accelerating the pathology.…”

Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology

“…In fact, ubiquitination of a-syn has been linked to the aggregation of a-syn in dopaminergic cells (Rott et al 2008). In a cellular model, the levels of ubiquitination correlate with that of a-syn oligomers and UPS dysfunction (Martins-Branco et al 2012), shifting the burden of a-syn degradation to the ALP. Further studies have also shown that ubiquitination of a-syn by the Co-chaperone carboxylterminus of Hsp-70-Interacting Protein (CHIP) can act as a molecular switch where the E3 ubiquitin ligase activity of CHIP drives a-syn toward lysosomal degradation (Shin 2005;Tetzlaff et al 2008).…”

Limelight on Alpha-Synuclein: Pathological and Mechanistic Implications in Neurodegeneration

“…Genetic mutations [185,186] and downregulated expression levels in enzymes [187], which mediate the proteasomal pathway, have, furthermore, been linked to familial and juvenile forms of PD. Moreover, the hydrolytic activities of proteasomes within the SNpc of PD patients are significantly reduced [188,189], as compared to normal controls. For these reasons, degradation of ASYN was initially thought to occur exclusively via the UPS and earlier studies were primarily focused on evaluating impairments within this system [190][191][192][193][194][195].…”

“…The pathways involved in regulating ASYN clearance remain contentious, however, a culmination of evidence suggests a mechanism that is multifactorial, which likely involves a dynamic variety of degradation-related systems, under various physiologic and diseased conditions. Several lines of evidence, for example, link degradation defects to mitochondrial dysfunction [189,[240][241][242][243][244]. Moreover, autophagic dysfunction has recently been implicated in transcellular transmission of ASYN [245], thus, providing further evidence of a fundamental and wide-reaching effect of misregulated ASYN degradation.…”