Prions are misfolded proteins that are associated with diseases such as BSE, Creutzfeldt-Jakob disease and scrapie. What makes prions particularly dangerous is their ability to induce properly folded proteins to convert into misfolded prion forms. This principle seems to be more widespread than previously thought. Dr. Mathias Jucker from the University of Tübingen and his American colleague Lary Walker from Emory University have put forward a hypothesis according to which neurodegenerative diseases such as Alzheimer’s are – similarly to prions - caused by misfolded proteins that aggregate into harmful seeds.
According to the prion principle, a single, misfolded protein would – at least in theory – be sufficient to create huge numbers of misfolded proteins because the newly formed misshapen proteins trigger a chain reaction that produces large amounts of misfolded proteins. Alzheimer’s disease, which is characterized by the presence of insoluble amyloid plaques in the brain, predominantly occurs in the elderly, and in particular in people over 65. However, spontaneous protein misfolding can occur at any age, even the juvenile protein biosynthesis machinery makes mistakes. Therefore, the question as to why such large numbers of misfolded proteins aggregate at a comparatively older age still remains to be answered.
Prof. Dr. Mathias Jucker from the Hertie Institute for Clinical Brain Research (HIH) and the German Centre for Neurodegenerative Diseases (DZNE) in Tübingen comments: “The misfolding of proteins occurs randomly. However, in young people, the cellular repair mechanisms intervene immediately and eliminate misfolded proteins. In older people, the repair mechanisms themselves are defective and misfolded proteins are at some stage no longer recognized as such and are therefore no longer degraded.”
The misfolded proteins form prion-like seeds that induce properly folded proteins to convert into the misfolded form. This stimulates the aggregation of misfolded proteins until a point of no return is reached, i.e. the point at which the aggregates can no longer be dissolved. The aggregates increase in size and number, and will eventually compromise neurological functions and develop into disease.
The hypothesis has since been substantiated by experiments carried out in Tübingen (Jucker) and in Atlanta, USA (Walker). Walker and Jucker published their hypothesis in the journal Nature in 2013. “Neurogenerative diseases are the price we pay for our longevity,” says Jucker. The self-propagation of pathogenic protein aggregates might not only explain the development of Alzheimer’s but also Parkinson’s and other neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis). A misfolded protein known as TDP-43 plays a key role in the pathogenesis of ALS and abnormal alpha-synuclein in the pathogenesis of Parkinson’s.
In the case of Alzheimer’s, Jucker assumes that aggregates of misfolded, extracellular amyloid-ß proteins are crucial in the development of the disease. Normal, soluble amyloid-ß proteins are involved in the transmission of information between nerve cells. In addition to amyloid-ß, there is another protein that is wrongly folded in Alzheimer’s brains. This protein (Tau) is normally abundant in the central nervous system where it stabilizes intracellular structures (microtubules). However, in Alzheimer’s disease, the protein is defective and no longer able to stabilize microtubules.
Jucker however believes that aggregates of misfolded amyloid-ß proteins are the major cause of Alzheimer’s disease. He bases his assumption on studies that explore the familial predisposition for Alzheimer’s. “In families with a defective amyloid-ß gene, 50% of the offspring will also develop Alzheimer’s and all of them will have the same amyloid-ß defect. For me, this is convincing evidence that misfolded amyloid-ß is the determining cause of Alzheimer’s, at least in familial cases,” says Jucker.
The molecular mechanisms of Alzheimer’s disease are as yet poorly understood. “The aggregation of misfolded proteins triggers a process that is possibly as yet unknown, and which leads to Alzheimer’s,” says Jucker. The brain region from where the protein aggregates spread to other regions also seems to play a role in the development of Alzheimer’s. “In Alzheimer’s, the misfolded proteins spread from the cortex from where they migrate into the subcortical brain area. In Parkinson’s disease, the aggregates spread from the brain stem to the cortical area. These differences are one of the great mysteries we are trying to solve. The big nerve cells in the brain stem produce such large amounts of amyloid-ß that it would be easy to assume that Alzheimer’s disease develops from here. The way we see things is that the spread of the misfolded proteins depends on how well the affected regions are able to deal with the misfolded proteins. We believe that this depends on the different neuronal activities and repair mechanisms. But we do not yet know how,” says Jucker.
All this is made even more difficult by the fact that a single protein can appear in many different misfolded forms. And these forms might differ in their toxicity. Or they might not be toxic at all. Jucker believes that this is supported by the fact that Alzheimer’s patients display different disease patterns. In mice, Jucker has shown that specific types of amyloid-ß misfoldings can be passed on to ‘normal’ proteins without necessarily leading to neurodegenerative diseases. So the question is: is the prion principle perhaps not always fatal?
Jucker does however not believe that every misfolding is a mistake; in fact, he believes that quite the opposite is the case. “Learning effects are controlled at the molecular level by folding states. Protein folding, which is the on- or off state of a protein, can function as an information store, much like the 0/1 alternative in computers,” explains Jucker. With this in mind, he finds the observation from the animal kingdom, i.e. that protein aggregates of this kind can dissolve again under altered conditions, quite exciting. Jucker has another hypothesis: “Every protein has the tendency to fold wrongly; for structural reasons, smaller proteins tend to fold wrongly more frequently than bigger ones. This option is the basic prerequisite for using proteins as an information store,” says Jucker. He further speculates whether long-lived organisms like humans have relatively big proteins because a long life requires proteins that are relatively resistant to misfolding. He is fascinated by this and is convinced that many exciting discoveries will be made. “We have reached the point where we know that protein misfolding is of crucial physiological function, but we do not yet know why,” says Jucker who, together with his team of 30, is working towards shedding more light into the darkness surrounding the role of misfolded proteins in the pathogenesis of neurodegenerative diseases.
Further information:Hertie Institute for Clinical Brain Research (HIH)Centre of Neurology, University Hospital of TübingenProf. Dr. Mathias JuckerOtfried-Müller-Str. 2772076 TübingenTel.: +49 (0)7071 29-87606E-mail: mathias.jucker(at)uni-tuebingen.de