In 1997, scientists reported finding a genetic mutation for a common brain protein called alpha-synuclein in affected members of the Contursi kindred—an Italian-American family with a rare inherited form of PD. This protein was subsequently found to be a major component of Lewy bodies and Lewy neurites—the pathological hallmarks of regular idiopathic PD. Many other intriguing alpha-synuclein findings followed. Affected members of another genetic kindred—the Iowa kindred––were shown in 2003 to have multiple copies of the normal alpha synuclein gene. As Rush University neuroscientist Jeff Kordower said, it indicated, “the only defect you have to have is too much synuclein and you get Parkinson’s.” Then in 2008, autopsies of fetal grafts performed in the 80s and 90s revealed alpha-synuclein-filled Lewy bodies in some of the grafted fetal neurons. After a decade, the eight-week old fetal dopamine cells had ended up catching an old person’s disease and showing classic Parkinson’s pathology. This led scientists to propose a new pathological mechanism for PD, whereby mis-folded alpha-synuclein clumped together into toxic aggregates and spread from neuron to neuron in a prion-like manner inside the patient's brain.
If alpha-synuclein is the bad actor in PD, then how might it be stopped? Therapies might target the way the molecule folds, either keeping it in its native state or encouraging it to switch to a stable non-aggregating conformation. Other strategies might include ways to help the body dispose of unwanted alpha-synuclein. Three papers report incremental progress towards these goals. At the Genetics Society of America’s 54th Annual Drosophila Research Conference in Washington D.C., Daniel Segal et al reported using the molecular chaperone mannitol to break up alpha-synuclein aggregates in the brains of fruit flies. Chaperones normally play a role in preventing newly synthesized proteins from mis-folding and forming non-functional aggregates. These results appear at odds with those just reported by the University of Pennsylvania’s Virginia Lee. Using her laboratory’s in vitro cell model of alpha-synuclein pathology, Lee seeded aggregates and then observed whether the cell’s mechanisms for chopping up and disposing of molecular garbage were up to the job. Lee says they weren’t. She writes, "these aberrant clumps in cells resist degradation as well as impair the function of the macroautophagy system, one of the major garbage disposal systems within the cell."
In a third paper, Stultz et al used computer modeling to explore the variety of ways this 140 amino acid protein could fold. The MIT team found that most of the time alpha-synuclein exists as single molecules switching between numerous disordered states. But the computer model indicated that groups of three and four alpha synuclein molecules can theoretically assemble to form trimers and tetramers, a small subset of which of which adopt stable and rigid helical conformations that resist aggregation. If true, this fits with recent reports by Harvard’s Dennis Selkoe and Brandeis’ Thomas Pochapsky and Gregory Petsko of finding such stable tetramers in the laboratory; reports that other labs have found hard to replicate.
If this pans out, then a drug that forced alpha-synuclein to adopt the rigid tetramer conformation could in principle prevent the aggregation of alpha-synuclein and slow, stop or reverse PD.
But given that these scientists are working in Petri dishes, fruit flies and computers rather than humans, such therapeutic tools are almost certainly a very long way off.
