The neurological damage that comes with mad cow disease or other prion disorders could be reversible if caught early on, says a study from Giovanna Mallucci and John Collinge at the Institute of Neurology in London. Their work, published in today’s Neuron, shows that depleting the brain of normal prion protein can cure mice with early symptoms of prion neurotoxicity. The strategy, which stops the conversion of normal protein to a toxic conformation in neurons, reversed behavioral defects, synaptic dysfunction, and brain pathology in the mice. The demonstration of a successful intervention after the first behavioral effects appear, but before neuron loss commences, shows that the brain can repair the initial damage in this protein misfolding disease.
The results define a potential window of opportunity for treating prion disease in humans, with ramifications for Alzheimer disease and other neurodegenerative conditions. In an accompanying commentary, Howard Federoff and Timothy Mhyre of the University of Rochester, New York, frame the challenge. “The extension of this general approach of defining a reversible phase and enabling interventions to the more common protein misfolding diseases such as Alzheimer’s and Parkinson’s should be strongly encouraged,” they write.
Prion disease results when infectious, misfolded prion proteins (in this case, the scrapie prion, PrPsc) propagate a neurotoxic conformation by inducing the misfolding of normal prion protein (PrPc). In their previous work, Mallucci, Collinge, and colleagues showed that endogenous PrPc serves to fuel the toxic fire of PrPsc infection (see ARF related news story). In that study, they used neuron-specific Cre recombinase expression to show that deleting the gene for PrPc in neurons of transgenic mice after infection reversed the appearance of spongiform prion pathology in the hippocampus and protected the mice from developing neurodegeneration and prion disease. Their manipulations did not stop the accumulation of PrPsc, which continued due to the presence of glial-derived PrPc. From this, they concluded that conversion of PrPc inside neurons was responsible for disease.
Now they extend these findings by showing that the early hippocampal spongiform pathology in those mice is accompanied by defects in memory and in spontaneous burrowing behavior. Both are tied to hippocampal function, and both improve after PrPc is depleted. Recovery is long-lasting, with mice up to 30 weeks old showing no ill effects despite massive PrPsc accumulation. This is consistent with the researchers’ previous results, which showed the mice survived to a normal old age with normal function.
The behavioral changes correlated with synaptic dysfunction. Electrophysiological recording from hippocampal slices revealed a loss of activity after prion infection. At the same time, they did not see reductions in synaptophysin, suggesting that synaptic structure was not yet affected. After PrPc deletion, they saw a rapid recovery of normal synapse function.
“These data now lead to the hope that early intervention in human prion disease will not only halt clinical progression but allow reversal of early behavioral and cognitive abnormalities,” the authors conclude. They hold out a similar hope for AD as well, where evidence from animal models is mounting that soluble Aβ oligomers may cause reversible neuronal dysfunction and cognitive defects before neuron death, and independent of β amyloid deposition.
The importance of this work is fourfold, write Federoff and Mhyre in their commentary. First, the work identifies a clear stage of reversibility, and second, it shows that young brains can compensate for injury after PrPc depletion. (One question they raise is whether the same results would be obtained in older mice, when the ability for functional recovery might be diminished.) In addition, they say, the work “heralds an era in therapeutics development for neurodegenerative diseases involving protein misfolding. Finally, the findings of this study make evident the need to better identify patients earlier in their disease course, when reversal and/or treatment of pathophysiological processes may be feasible.”—Pat McCaffrey