Proteins are a little like laundry: folding matters. When folded properly, proteins can go about their intended business as the machinery of the cell, responsible for its structure and function. A misfolded protein or two can be an annoyance, temporarily throwing off the order of the cell but easily handled by a cell’s internal janitors. But when those misfolded proteins pile up like rumpled clothes across a messy room, the whole system can collapse, leading the cell to an early demise.
These catastrophic failures of folding may be the cause of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Lou Gehrig’s Disease (amyotrophic lateral sclerosis). When pathologists look at the brains of people who die from these conditions, they find unusual changes, with missing neurons and/or abnormal deposits known by names like plaques, tangles, and Lewy bodies. As imaging techniques have improved, scientists have traced these abnormalities back to protein misfolding, with the accumulated defects leading to intracellular traffic jams and even cell suicide.
Experts in the protein folding field met October 29th at the University of Chicago as part of a special symposium organized by the Chicago Biomedical Consortium, a partnership between Chicago-area research institutions. A succession of experts talked about the intricate origami of folding polypeptide structures into functional proteins, the cellular mechanisms that help regulate that process, and the consequences when those mechanisms fail and misfolded proteins are allowed to aggregate into dangerous clumps.
“The ability of polypeptide chains in vivo to fold correctly into their native states with sufficient frequency for them to be able to execute their functions in a living organism is one of the most fundamental and remarkable phenomenons in biology,” said Sangram Sisodia, professor of neurosciences at the University of Chicago. “Despite these regulatory systems, protein misfolding and aggregation do occur, particularly as organisms age, and cause devastating diseases.”
Scott Brady of the University of Illinois at Chicago illustrated those diseases with the famous people they are associated with: Muhammad Ali and Parkinson’s disease, for example, or Woody Guthrie and Huntington’s. Brady then outlined the reasons why a pile of misfolded proteins can be so troublesome to neurons – many of which are long, skinny structures (as long as a meter in humans) that must transport proteins from one end to the other. Should an aggregate of erroneous proteins occur anywhere along that long stretch, it could cause a traffic jam fatal to the cell. Brady’s laboratory has repeatedly demonstrated this process in what is, thanks to their long, wide axons, a favorite animal model of neurobiologists: the squid.
“You may be wondering what calamari has to do with all this,” Brady said. “No, squids do not get Alzheimer’s disease, but they react to the toxic proteins in Alzheimer’s just as well as mammalian systems.”
That was demonstrated by expressing gene variants know to be associated with Huntington’s or Alzheimer’s in squid axons, which caused misfolded proteins to form and block forward and backward traffic in the cell. Steven Finkbeiner, of UCSF, saw a similar phenomenon with the abnormally long “huntingtin” proteins responsible for Huntington’s disease, which formed clumps that some cells could clear, and some cells could not. In those neurons where the natural trash disposal system was overwhelmed by the aberrant proteins, the result was death. Boosting those cellular garbagemen could be a potential strategy for fighting back against these neurodegenerative diseases, Finkbeiner said.
If that’s the case, it’s important to understand the trash disposal mechanisms that a cell has to use. Randal Kaufman (University of Michigan) and Ana Maria Cuervo (Albert Einstein College of Medicine) provided that knowledge to the symposium, elucidating the multiple ways by which a healthy cell can nullify a misfolded protein’s threat. Protein errors can be diverted to the endoplasmic reticulum, the “quality control” center of the cell, Kaufman said, where they can be refolded or degraded for recycling. But a sudden burst of protein production can overwhelm the endoplasmic reticulum and cause it to fail. Similarly, Cuervo outlined how cells can encase dangerous proteins in cannibalistic bubbles called autophagosomes, which loosely translates to self-eating compartments. But defective proteins, like the extra-long huntingtins, evade those bubbles or make them clump together, a wrench in the cellular gears of trash disposal.
The protection provided by endoplasmic reticula and autophagosomes may also diminish with age, a theory for why Alzheimer’s and Parkinson’s disease usually doesn’t produce symptoms until late in life. Laboratory studies have found some potential for antioxidants and a caloric restriction diet for reinforcing the cell’s defenses against misfolded proteins, but further studies are needed. Testing those strategies are high priority for diseases that have proved frustrating thus far, despite several treatments that once seemed promising.
“They all have one thing in common: none of them work,” Brady said. “What we have to do is find something that addresses the underlying molecular basis of these diseases, and see if we can intervene at that level.”