How useful is the laboratory mouse to research on neurodegenerative disease? Anybody who’s dissected a mouse knows that its organs are strikingly similar to textbook pictures of human organs. However, the brain is a special case. Though there are broad similarities, such as that both humans and mice have a hippocampus, humans have many more neurons, many more connections between them, and vastly more intellectual capacity. With this in mind, some neurobiologists advocate using mice to study biochemical pathways that may underlie neurodegenerative disease and not the symptoms or the clinical outcomes. The latest breakthrough in research on neurodegenerative diseases, announced in an October 9 paper in Science Translational Medicine by Julie Moreno and colleagues, is a good example of this approach.
Moreno and colleagues hypothesized that neuronal degeneration, characteristic of Alzheimer’s, Parkinson’s, and prion diseases, occurs because of an inappropriate response to misfolded protein. In all of these diseases, the neurons encounter lots of misfolded protein, though the identity of the protein differs by disease. In Alzheimer’s disease, the misfolded protein is beta-amyloid, in Parkinson’s it is alpha-synuclein, and in prion disease it is PRNP. The usual cellular response, called the unfolded protein response, is to halt all new protein production for a short period, during which the external stressor that was misfolding protein would hopefully go away, and then resume normal life. However, in neurodegenerative diseases the stressor is continuous, leading Moreno and colleagues to hypothesize that neurons would shut down protein production for too long, starving themselves of essential synaptic proteins and dying. The authors note that brains of patients with Alzheimer’s, Parkinson’s, and prion disease have been found to display phosphorylated PERP and phosphorylated eIF2α, both markers of unfolded protein response.
Components of the unfolded protein response are conserved between humans and mice, making mouse studies appropriate. Moreno and colleagues focus on a mouse model of prion disease. They cause disease by infecting mice with prion-containing brain homogenates and then give a chemical inhibitor of PERK, a protein kinase that is the main effector of the unfolded protein response. Twelve weeks after prion infection and three weeks after beginning PERK inhibitor treatment they see dramatically reduced neurodegeneration compared to mice that received the prion infection but not the PERK inhibitor. Whereas, the untreated mice are terminally ill at twelve weeks after infection, the PERK-inhibitor-treated mice show normal behavior, though they do lose about 20% of their body weight, probably due to the inhibition of the unfolded protein response, an important homeostatic response, in all tissues of the body. In all, the results are consistent with the hypothesis that prion disease kills neurons by making them turn off their protein synthesis for too long.
The results are exciting, but the authors’ cautious interpretation is also reason to celebrate. Moreno and colleagues use their mouse experiments to test a molecular biology hypothesis about the cause of neuronal death, focusing on fundamental aspects of neurodegenerative disease that really are shared between mice and humans. The logical next step would be to delve deeper into the molecular biology of the unfolded protein response as it relates to neuronal survival. And because this paper uses mice appropriately, it is not difficult to believe that this mouse cure is bringing the human cure of neurodegenerative diseases a bit closer.