Jonathan Eledge, Ms. Jennifer Deger, Ashley Nilson, Urmi Sengupta, Dr. Rakez Kayed
University of Texas Medical Branch
Neurodegenerative diseases are pathologically characterized by abnormal accumulation of one or more proteins into aggregates. For example, α-synuclein and tau, among others, have been implicated in a number of diseases, including Alzheimer’s Disease (AD) and Dementia with Lewy Bodies (DLB). Increasing evidence suggests that oligomeric forms of amyloidogenic proteins are the true toxic entity, rather than their large fibrillary aggregates. One of the possible mechanisms by which toxic oligomers accumulate and cause more widespread deleterious effects is through proteasome dysregulation.
Protein turnover is required for all cells to maintain homeostasis. Proteasomal degradation is one natural mechanism, in addition to autophagy, for breaking down mis-folded proteins or aggregates. Mis-folded proteins are covalently tagged with either ubiquitin molecules or ubiquitin-like modifiers (SUMO) that are recognized by the proteasome for degradation. Both tau and α-synuclein have been demonstrated to independently downregulate proteasome function, but their modification via poly-ubiquitination or sumoylation has been overlooked.
The aim of this study is to characterize the role of covalent modifiers and their involvement with oligomeric α-synuclein and tau in proteasomal dysfunction in neurodegenerative diseases. Postmortem brain tissues from AD, DLB, and age-matched non-demented control subjects were characterized via immunofluorescence, and Western blot analyses using antibodies against ubiquitin and SUMO. We further quantified the bands from Western blot analyses and fluorescent signal using ImageJ. Statistical analysis and graphs were generated using GraphPad Prism.
From this study we observed a significant difference in proteasomal targeting of the toxic aggregates. Further studies will allow us to elucidate how these toxic oligomers are allowed to bypass the homeostatic unfolded protein response machinery. Such information is valuable for the purpose of therapeutic intervention.