New brain disorder tools results in new drugs
used to reproduce a change in the axon's shape that is
characteristic of neurodegenerative disorders. The model provides a
new road to discovering new kinds of drugs for the treatment of
these disorders.
The model's construction is the first of its kind in a highly simplified biophysical model system and could give new insights into the specific mechanisms that contribute to complex brain diseases.
Current therapies for the treatment of Alzheimer's and Parkinson's diseases only go as far as treating symptoms and not the root cause of the disorders. With this new tool, researchers hope to go one step further and isolate the destructive mechanisms.
This model, produced in the laboratory of Paul Weiss, professor of Chemistry and Physics at Penn State University has the essential features of an axon, including a lipid membrane that encloses a "cytoskeleton" scaffolding, which produces the axon's shape.
The outer membrane was prepared to contain a very small amount of dye molecules that are sensitive to ultraviolet light. Shining light on the artificial axons initiated a photochemical reaction that produced highly reactive "free radicals" and triggered a catastrophic oxidative-stress reaction.
The result was that the previously protruding microtubule cytoskeleton collapsed into a constricted and deformed structure resembling a string of beads, the same morphology observed during the degeneration of actual neurons.
However, the model reproduced this highly characteristic "beading" or "pearling" even though it does not include proteins that were previously thought to be essential for causing this kind of axon destruction.
"There is tremendous urgency right now to determine which processes cause the destructive mechanisms that we see in neurodegenerative diseases," said coauthor and assistant professor of Veterinary and Biomedical Sciences, Anne Milasincic Andrews.
"Our study shows that oxidative stress, whatever its origin, is capable of causing the cytoskeleton of this artificial system to collapse in the same way that it does in diseased or aging brains."
The study also revealed many specifics about the process of axon collapse. For example, the degradation rate is faster when the lipids comprising the membrane have more multiple bonds (they are more highly unsaturated).
The researchers also added free-radical scavengers, such as vitamins C, E, and K, to the model system and found that these vitamins delayed or prevented the degradation of the cytoskeleton.
"These antioxidant vitamins neutralized the free radicals before they had a chance to degrade the model axon," said Paul Weiss, professor of Chemistry and Physics at Penn State university.
"Simple models also allow us to build more complicated hypotheses, which later can be tested in complex living systems, such as laboratory animals. We plan to build into our model the different brain chemicals that have been implicated in neurodegenerative processes to see which are the good and bad actors, which are the most effective in promoting the radical attack from the membrane to the interior of the axon and which are the best at disabling free radicals."
The research will be described in a paper to be published in the 4 April 2006 issue of the >Proceedings of the National Academy of Science.
