A New Way to Fight Neurodegenerative Diseases?


by Jim Schnabel

December 19, 2013

Prions kill mice in much the same way that they kill humans-swiftly, rendering the brain spongelike from extensive neuronal losses within months of infection. No one has found a plausible therapy that can stop a prion disease. But there is new hope that such a therapy can be devised, and that it might work against other neurodegenerative diseases as well, including Alzheimer's and Parkinson's.

In a paper published on October 9, 2013 in Science Translational Medicine, a team led by prion researcher Giovanna Mallucci at the University of Leicester showed that an experimental, enzyme-inhibiting drug, GSK2606414-originally developed as a potential cancer treatment-stopped or at least greatly slowed prion disease in transgenic, highly prion-susceptible mice.

What is a Prion?

Disease-causing prions--particles that self-propagate and infect tissues despite containing no genetic material--were long supposed to be "misfolded" single copies of the naturally occurring neuronal PrP protein. The idea, which helped earn neurologist Stanley Prusiner the 1997 Nobel Prize in Physiology or Medicine, was that one of these misshapen and presumably toxic PrPs, whenever it came into contact with an ordinary, healthy PrP protein, would somehow induce the latter to become misshapen in the same way-and this molecular chain-reaction could spread through the brain like an infection.

However, researchers now widely believe that the agent of infection in prion disease is not a misfolded single copy of PrP, per se, but a cluster of several copies (a.k.a. an oligomer) of PrP. Oligomers of amyloid beta, tau, and alpha synuclein have been linked to Alzheimer's, Parkinson's, and other neurodegenerative diseases. Oligomer formations of proteins are not inherently pathogenic-many proteins evolved to perform their normal functions while conjoined in that way. But neurodegenerative-disease-linked oligomers are thought to share features that make them somehow toxic to brain cells. Just as importantly, these disease-linked oligomers also appear to be self-propagating-by acting as templates for individual protein copies to cluster together into new oligomers. 

Twelve weeks after having disease-causing sheep prions injected into their brains, all untreated mice showed unmistakable signs of prion disease. By contrast, treated mice had few behavioral signs and only mild brain damage, and that was true even of mice that had been left untreated until nine weeks post-infection, when early disease signs had already begun to surface. Though active and otherwise seemingly well, the treated mice lost weight-possibly as a side effect of the treatment-enough that by the UK's strict animal welfare rules they had to be euthanized soon after 12 weeks. But up to that point the treatment clearly had protected the animals from severe neurodegeneration and death.

Mallucci's group reported a similar result last year in Nature, using a more direct-but less clinically applicable-genetic targeting of the enzyme in question. This study, however, is "the first in which a chemical compound has been given orally and has provided such profound neuroprotection," Mallucci says.

A general mechanism of neurodegeneration?

Mallucci's mouse study would be noteworthy even if it were relevant only to prion diseases. Although they afflict people rarely, and usually without an obvious cause-Creutzfeldt-Jakob disease (CJD), the principal human prion disease, has an annual worldwide incidence of only about one or two cases per million people-these maladies are particularly fearsome. They are typically fatal within months of diagnosis, and can sometimes be transmitted to humans from other species, as they were in the 1990s via beef products contaminated with cattle prions. Scientists are trying to devise drugs and vaccines for prion diseases, but until now nothing has shown much promise.

However, the main impact of Mallucci's study may be in regard to neurodegenerative diseases generally. The enzyme she targeted, known as PERK, helps activate a basic stress response in brain cells, the "unfolded protein response" (UPR), which is triggered by an overload of misfolded, aggregation-prone proteins or by protein aggregates themselves. The buildup of such aggregates-of amyloid beta and tau proteins in Alzheimer's, for example, and of PrP protein in prion diseases (see sidebar)-is a central feature of most known neurodegenerative disorders.

Studies in the past few years have found signs of UPR activation in autopsied brain tissue from patients with Alzheimer's, with Parkinson's, and with a tau-associated neurodegenerative disorder (tauopathy) known as fronto-temporal lobe dementia. In a way, this isn't surprising: UPR activation should occur at least transiently in response to an excess of unwanted protein aggregates, and it should help brain cells. But there has been an increasing suspicion that these diseases feature a chronic UPR activation that ends up harming brain cells.

For example, in a study reported in August 2013, a group led by Eric Klann at New York University found that blocking UPR activation in a standard transgenic mouse model of Alzheimer's prevented the mice's usual signs of disease: a loss of neuronal synapses (connection points to other neurons) and memory deficits.

Why would a chronically activated UPR harm neurons? One of the main UPR signaling pathways leads to the shutdown, via PERK or three other known kinase enzymes, of the cellular factories that normally translate genetic material into proteins. Neurons with an activated UPR therefore stop making new proteins. This shutdown gives the cells "breathing room" in which to reduce-using other mechanisms-the overload of unwanted proteins such as PrP or amyloid beta aggregates. But it is meant to be only temporary: A neuron can't long survive if its ability to synthesize new proteins is broadly blocked.

Klann suspects that in the case of Alzheimer's, UPR-related shutdowns of protein synthesis in neurons are initially protective, but in an aging brain the constant stimulation by amyloid beta-most likely in the form of small aggregates known as oligomers-eventually leads to a dysregulated UPR. "You have this chronic upregulation of what was initially a protective effect," he says, "and so you chronically decrease the ability of neurons to synthesize new proteins in response to the appropriate stimuli, which leads to impaired plasticity and memory deficits." And perhaps ultimately to neuronal death, as Mallucci's study hints. (Prion-diseased mice are one of the few animal models of neurodegenerative disease that exhibit the massive loss of brain cells seen in humans.)

The good news is that restoring protein synthesis may be enough to keep brain cells from dying, even as the presumed buildup of protein aggregates continues. Conceivably it would reduce the aggregate problem too. "We have some evidence from lab dish studies that the UPR's activation contributes to tau pathology in Alzheimer's and other tauopathies," says Wiep Scheper, a researcher at VU University Medical Center in Amsterdam who co-authored a commentary on the Mallucci study. [See also "The How of Tau."]

Thorny details

Restoring the UPR-related shutoff of protein synthesis isn't necessarily an easy therapeutic strategy. Doing so by inhibiting PERK, for example, can cause severe side effects, since PERK-like enzymes have other functions elsewhere in the body. "If you completely inhibit PERK, you will destroy pancreatic beta cells, causing diabetes; you will damage the liver and probably bones too," says Scheper. The mice in Mallucci's study did show modest rises in blood sugar levels, and possibly also in connection with PERK inhibition, the animals lost a lot of weight. "Our study was a good proof of principle, but clearly the compound we used will not go into people," Mallucci says.

Her lab, Scheper's, Klann's and others are now looking for other ways to dial down the UPR and its protein-synthesis shutoff. "Maybe we should be looking a bit further downstream in the UPR pathway, or finding ways to inhibit PERK's function more selectively," says Scheper. She adds that the UPR is an important response to cell stress that probably should never be switched off long-term, so an intermittent rather than a constant UPR inhibition might be another therapeutic approach, perhaps combined with the boosting of other cellular mechanisms that help clear unwanted protein aggregates. [See "'Good housekeeping' and healthy brain aging."]

 "It is definitely a promising approach to treating neurodegenerative diseases," Scheper says. "But at this point it still needs a lot more work."