Periz G, Lu J, Zhang T, Kankel MW, Jablonski AM, Kalb R, McCampbell A, Wang J. Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription. PLoS Biol. 2015 Apr;13(4):e1002114. Epub 2015 Apr 2 PubMed.
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University of Colorado
Periz et al. used a classic C. elegans genetic approach as a starting point to uncover a conserved cellular pathway that can limit the aggregation and toxicity of disease-associated variants of superoxide dismutase -1 (SOD1) and other proteins associated with neurodegenerative diseases. Through a fairly heroic process, they identified a rare double mutation that suppressed the toxicity caused by transgenic expression of human disease-mutant SOD1. They then used fly and human cell models to track down how these mutations worked together to ultimately activate processes that degrade abnormal proteins. A key finding was their demonstration that p53, a well-characterized regulatory protein known as the "guardian of the genome," played a central role in this protective process. Using cell culture, they demonstrated that drugs that (indirectly) activate p53 could promote the clearance of the toxic insoluble forms of mutant SOD1. They concluded that targeting p53 could be a potential wide-spectrum anti-proteotoxicity therapeutic strategy.
While this study gives a compelling demonstration that p53 can be activated to protect cells from toxic protein aggregation, there are caveats about this being a therapeutic route in human neurodegenerative disease. Because p53 is a multifunctional protein that can promote cell repair or cell death, calibrating its activation to be therapeutic and not deleterious seems inherently challenging. As a practical matter, activating FOXO proteins—previously well-established to combat multiple forms of cell stress—might be a better therapeutic approach. Despite an impressive array of experiments, the researchers did not introduce a loss-of-function mutation in worm p53 (in the cep-1 gene) into their double-mutant suppressed worms, so it is actually an open question whether the proposed mechanism of SOD1 toxicity suppression is at work in the worm model. As is always the case, interpretation of results from model systems is inherently limited by how closely the models reproduce human disease pathology. Many transgenic models significantly over-express disease-associated proteins, leaving it uncertain whether interventions that work in these models are targeting the relevant toxic processes, or just generic aggregating protein toxicity. Nevertheless, proteotoxicity appears to be an underlying factor in almost all age-associated neurodegenerative diseases, and understanding the cellular processes that moderate proteotoxicity is undeniably relevant to understanding these diseases.
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