Archaeal proteasomes effectively degrade aggregation-prone proteins and reduce cellular toxicities in mammalian cells.

The 20 S proteasome is a ubiquitous, barrel-shaped protease complex responsible for most of cellular proteolysis, and its reduced activity is thought to be associated with accumulations of aberrant or misfolded proteins, resulting in a number of neurodegenerative diseases, including amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Parkinson disease, and Alzheimer disease. The 20 S proteasomes of archaebacteria (archaea) are structurally simple and proteolytically powerful and thought to be an evolutionary precursor to eukaryotic proteasomes. We successfully reproduced the archaeal proteasome in a functional state in mammalian cells, and here we show that the archaeal proteasome effectively accelerated species-specific degradation of mutant superoxide dismutase-1 and the mutant polyglutamine tract-extended androgen receptor, causative proteins of familial amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy, respectively, and reduced the cellular toxicities of these mutant proteins. Further, we demonstrate that archaeal proteasome can also degrade other neurodegenerative disease-associated proteins such as alpha-synuclein and tau. Our study showed that archaeal proteasomes can degrade aggregation-prone proteins whose toxic gain of function causes neurodegradation and reduce protein cellular toxicity.