Abstract
α-Synuclein inclusion bodies are a pathological hallmark of several neurodegenerative diseases, including Parkinson’s disease, and contain aggregated α-synuclein and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin and the small ubiquitin-like modifier, SUMO-1. Cell culture and animal model studies suggest that misfolded, aggregated α-synuclein is actively translocated via the cytoskeletal system to a region of the cell where other factors that help to lessen the toxic effects can also be recruited. SUMO-1 covalently conjugates to various intracellular target proteins in a way analogous to ubiquitination to alter cellular distribution, function and metabolism and also plays an important role in a growing list of cellular pathways, including exosome secretion and apoptosis. Furthermore, SUMO-1 modified proteins have recently been linked to cell stress responses, such as oxidative stress response and heat shock response, with increased SUMOylation being neuroprotective in some cases. Several recent studies have linked SUMOylation to the ubiquitin-proteasome system, while other evidence implicates the lysosomal pathway. Other reports depict a direct mechanism whereby sumoylation reduced the aggregation tendency of α-synuclein, and reduced the toxicity. However, the precise role of SUMO-1 in neurodegeneration remains unclear. In this review, we explore the potential direct or indirect role(s) of SUMO-1 in the cellular response to misfolded α-synuclein in neurodegenerative disorders.
Highlights
Parkinson’s DiseaseParkinson’s disease (PD) is characterized by widespread intracellular inclusion bodies (Lewy bodies), composed largely of aggregates of the protein -synuclein
Aggresomes can be formed in neural cell culture under various conditions that result in the abnormal aggregation of cellular proteins and comprise amyloid-like -synuclein filaments and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin, and recently, neuropathological inclusion bodies have been found to accumulate the small ubiquitin-like modifier-1, SUMO-1 [14,15]
This crosstalk is considered to be made possible by the dual role of ubiquitination which acts as the protein degradation signal for both ubiquitin-proteasome system (UPS) and the selective mode of macroautophagy [35,45]
Summary
Parkinson’s disease (PD) is characterized by widespread intracellular inclusion bodies (Lewy bodies), composed largely of aggregates of the protein -synuclein. Lewy bodies are part of a protective cell response, namely the aggresome pathway, the cytotoxicity of abnormal soluble -synuclein aggregates is implicated as a key factor causing cell death. Intracellular -synuclein aggregates are found in a variety of other neurodegenerative diseases, including multiple system atrophy and dementia with Lewy bodies, the so-called -synucleinopathies, and are believed to form by a process involving the active translocation of soluble protein micro-aggregates along the microtubule network to converge on the microtubule organizing centre (MTOC/centrosome) [4,5,6,7]. Aggresomes can be formed in neural cell culture under various conditions that result in the abnormal aggregation of cellular proteins and comprise amyloid-like -synuclein filaments and a variety of recruited factors, including protein chaperones, proteasome components, ubiquitin, and recently, neuropathological inclusion bodies have been found to accumulate the small ubiquitin-like modifier-1, SUMO-1 [14,15]. We evaluate a range of factors that could provide links between SUMOylation and the toxicity of -synuclein aggregates in neurodegeneration
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