Alzheimer’s, Parkinson’s, and other major neurodegenerative diseases appear to have early, silent tipping points, at which toxic protein clusters start to build up faster than brain cells can safely dispose of them. There is evidence that these tipping points generally occur in middle age, in part because cellular systems that degrade and recycle unwanted protein formations start to decline in efficiency during these years (see “In Search of the Origins of Neurodegenerative Disease”). Some labs now are looking for ways to prevent specific neurodegenerative diseases by boosting these natural waste-recycling systems in brain cells—a strategy that, in principle, would keep our brains more youthfully free of harmful gunk.
“There’s a lot of evidence now that protein degradation and the accumulation of misfolded proteins are relevant to some aging-related diseases, and maybe to normal aging,” says Dan Finley, a professor of cell biology at Harvard Medical School.
Pumping up proteasomes
Cellular processes that limit or get rid of potentially harmful material are particularly important in the brain. The production of new neurons by stem cells occurs only in a small minority of brain regions, and so neurons that fail to keep their waste-recycling systems running efficiently are likely to die without being replaced.
One of the best-known of these recycling systems is the ubiquitin-proteasome system. Ubiquitin enzymes latch onto unwanted proteins and form chains that mark them for disposal, while proteasomes, roving structures that bristle with protein-cutting protease enzymes, do the disposing. Proteasomes can clear small protein aggregates (“oligomers”), can keep single copies of inherently aggregation-prone proteins at safe concentrations, and can dispose of proteins that have been altered to become more aggregation-prone, says Finley.
Finley’s lab, collaborating with the lab of fellow Harvard cell biologist Randall King, published a study in Nature Sept. 9, 2010, showing from test-tube and cell culture experiments that a natural enzyme, USP14, normally helps to regulate the proteasome system by trimming ubiquitin chains—in effect, limiting proteasomes’ ability to recognize and clear unwanted proteins and oligomers.
Finley and King and their colleagues screened thousands of small molecules until they found one—dubbed IU1—that could inhibit the activity of USP14. Applying IU1 to their cell cultures, they found that the drug sharply increased the ability of proteasomes to clear several cluster-prone proteins associated with neurodegenerative disease, including tau protein (seen in Alzheimer’s) and TDP-43 (seen in amyotrophic lateral sclerosis), as well as proteins dangerously altered by reactive oxygen molecules.
“Since submitting the paper we’ve found more potent derivatives of IU1, and we’re planning to test these in several mouse models of neurodegenerative disease,” says Finley.
The labs are currently finalizing an agreement with a private biotech partner to support this initial drug-development research. But Finley and King and their colleagues also hope to find new ways to influence the proteasome system. “There are a lot of credible drug targets in that pathway,” Finley says.
Another major waste-disposal mechanism in cells involves the lysosome—a roving, stomach-like sac filled with acids and strong enzymes. Lysosomes appear to have evolved to digest and recycle just about any biological material; they exist in the brain within neurons as well as in waste-clearing microglial cells, and seem better than proteasomes at disposing of larger protein aggregates.
Over the past few years, a number of labs have sought to boost a lysosome-using process known as “autophagy,” or self-eating, by which neurons recycle unwanted interior waste. Early work suggested that autophagy could be boosted with rapamycin, an immune-suppressing drug used by transplant recipients. Rapamycin works on autophagy by inhibiting a key growth-related signalling pathway in cells, known as the mTOR pathway.
“It works well in animal models and it’s a drug that’s already prescribed for chronic use,” says David Rubinsztein, a professor of molecular neurogenetics at Cambridge University. But rapamycin has significant side effects. “Our feeling was that we need drugs that have minimal side effects, especially if we’re going to be treating people, such as young people with Huntington’s disease mutations, who don’t yet have symptoms.”
Rubinsztein and his colleagues have subsequently found several other drugs that boost autophagy via non-mTOR pathways, including rilmenidine, an FDA-approved blood pressure drug that is considered safe for long-term use. “We’re excited by the safety of the drugs, and we also now have proof of principle in a range of animal systems,” Rubinsztein says. He and his colleagues plan to begin a safety trial of rilmenidine in Huntington’s patients this year to determine whether the drug is as safe in these patients as it seems to be in the general population.
Other labs are not far behind. In September 2010, researchers in the laboratory of neurologist Steven Finkbeiner at the University of California at San Francisco reported having found a set of drug compounds, structurally related to the chemical phenoxazine, that also boost autophagy in neurons. The compounds reduce the accumulation of mutant Huntingtin aggregates and protect neurons from early death, in a cellular model of Huntington’s disease. Since that work, Finkbeiner says, his lab has found even safer and more potent compounds, some of which are existing, FDA-approved drugs: “We’ve got plans to do work in a Huntington’s disease model, an ALS model, and an Alzheimer’s model.” he says. “We’re going to try to get this into the clinic as fast as we can.”
Attacking aging, too?
Biomedical researchers almost always aim their efforts at preventing or curing diseases. But in principle, boosting our natural cellular waste-recycling systems could also protect against the general protein buildup that seems to occur in so-called healthy aging. The relevant experiments haven’t yet been done in humans, but manipulations that powerfully boost the longevity of cells or animals often appear to do so, at least in part, by boosting autophagy or proteasomal clearance. “It’s not a focus of our research,” says Finley, “but I think it’s natural to wonder about it.”
Rubinszstein, too, says that the idea of enhancing these general clearance systems in older adults to boost the brain’s longevity represents “an attractive area for speculation.”