Role of small ubiquitin-like modifiers (SUMO) in neurodegeneration and Alzheimer's disease

Sumoylation is a post-translational modification by which small ubiquitin-like modifiers (SUMO) are covalently conjugated to target proteins. This reversible pathway provides a rapid and efficient way to modulate the subcellular localization, activity and stability of a wide variety of substrates. Consequently, sumoylation impacts disease pathways such as oxidative stress, protein misfolding and proteasome-mediated degradation. These events can contribute to the formation of abnormal protein aggregates associated with a number of neurodegenerative diseases. Similar to ubiquitin, SUMO co-localizes with these neuronal inclusions and, in some instances, the constituent proteins have been identified as substrates for sumoylation. Based upon these observations, it is our hypothesis that the SUMO pathway contributes to the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. This was supported by the demonstration that SUMO3 overexpression significantly upregulated the production of amyloid-beta (Abeta) peptides. Sumoylation-induced changes in Abeta were found to be independent of SUMO conjugation and indicated that SUMO3 could potentially impact the formation of amyloid plaques in AD. The two natively unfolded proteins tau and alpha-synuclein have also been identified as novel SUMO substrates. These proteins form the basis of pathological inclusions corresponding to neurofibrillary tangles in AD and alpha-synuclein-containing Lewy bodies found in Parkinson's disease, respectively. Finally, an exploratory quantitative proteomic study has isolated potential SUMO substrates specifically upregulated in response to proteasome inhibition, a common feature in brain aging and neurodegeneration. Taken together, these original findings indicate that SUMO may contribute to Alzheimer's disease and neurodegenerative processes through several possible cellular pathways.