Building up degradation
A trio of papers makes a case for purging neurotoxic misfolded proteins from neurons by stimulating two protein degradation processes: autophagy and proteasome-based proteolysis.1-3The findings could apply to neurodegenerative disorders such as Parkinson's disease and Huntington's disease, in which accumulation of misfolded intracellular proteins is a common feature.
Autophagy involves the engulfment of cytoplasm into membrane-bound compartments called autophagosomes, which deposit their cargo into acidic, protein-dissolving lysosomes. Proteasome-based proteolysis results inselective degradation of proteins marked by the covalent addition of ubiquitin. Both processes are part of the normal cellular protein-recycling machinery.
Previous cell culture and mouse studies havesuggested that defects in protein turnover exacerbate the toxic effects of misfolded proteins thought to underlie PD and HD.4
Although the precise cause of toxicity by misfolded proteins in neurodegenerative disease is a contentious subject, coming up with a way to get rid of those proteins could render the debate moot.
"There are a number of ways that it might be beneficial to stimulate protein clearance," said Steven Finkbeiner, senior investigator and associate director of the Gladstone Institute of Neurological Disease and professor of neurology and physiology at the University of California, San Francisco."If you believe that protein misfolding causes disease by producing a toxic form of the protein, stimulating autophagy can clear away this aggregated protein. If you believe that misfolded proteins cause disease by dysregulating the