Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein

Abstract

Parkinson's disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded αsynuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded α-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded α-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adenoassociated viruses to co-express A53T α-synuclein and the ubiquitinated reporter protein Ub G76V-GFP in rat SNpc. We found that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of α-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for α-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo.

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

“…The latter may remain inaccessible to larger, insoluble aggregates, preventing their effective degradation [76,77]. In fact, many oligomers and aggregated proteins have been shown to inhibit UPS activity [7,55,78,79]. When the UPS is impaired, an upregulation of autophagy may occur to enable the clearance of larger aggregates [67,80].…”

“…Still, when UPS is impaired, autophagy activation may cope with α-syn clearance to rescue cell survival [80]. This is important since misfolded α-syn overexpression early impairs UPS function preceding the onset of behavioural deficits and DA neuron degeneration, and this is associated with selective accumulation of neurotoxic α-syn phosphorylated at the serine 129 residue [79].…”

BAG5 Promotes Alpha-Synuclein Oligomer Formation and Functionally Interacts With the Autophagy Adaptor Protein p62

“…Importantly, however, the complex interplay between p62, BAG5, alpha-synuclein, the UPS, and the ALP is likely not captured by any of these mechanisms in isolation. Indeed, p62 acts as a molecular bridge between the UPS and ALP and facilitates the upregulation of ALP activity following UPS inhibition (Lim et al, 2015;Liu et al, 2016), BAG5 has modulatory effects on the ALP and UPS via its interaction with CHIP (Kalia et al, 2011), LRRK2 (Beilina et al, 2014), and parkin (Kalia et al, 2004), and misfolded alpha-synuclein is known to induce dysfunction in both the UPS and ALP (Winslow et al, 2010;McKinnon et al, 2020). Furthermore, while the interaction between BAG5 and p62 does not appear to require Hsp70, it is possible that both Hsp70-dependent and independent pathways are relevant to the function of a BAG5-p62 interaction given the known co-chaperone activity of BAG5 (Kalia et al, 2004).…”

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

“…HRI controls responses to aggregating αsynuclein a-synuclein, a protein that accumulates and forms aggregates in neurons in Parkinson's disease and other synucleinopathies may impair the UPS early in the disease process (27) and is dominantly cleared from the cytosol by autophagy-mediated clearance (28). To monitor the role of HRI in controlling the accumulation of a-synuclein, we used a luciferase reporter system for which a split form of the luciferase enzyme is associated as two hemi-luciferase moieties in fusion with a-synuclein (asyn L1 and asyn L2).…”