The origin of mysterious filaments that aggregate in the brains of people with Parkinson鈥檚 and other neurodegenerative diseases may have been identified.
The barrier between the nucleus and the rest of the cell grows leakier with age, say researchers, allowing proteins in from the rest of the cell. One of these proteins, called tubulin, forms long filaments that have been found to take over the nucleus and may damage the chromosomes.
鈥淧athologists had been aware of these filaments for more than 100 years and their frequency has been shown to increase with age, but their origin was mysterious,鈥� says at the Salk Institute of Biological Sciences in La Jolla, California.
Advertisement
In Parkinson鈥檚 patients, tubulin filaments are particularly prevalent in part of the brain called the substantia nigra 鈥� a region that produces the neurotransmitter dopamine and is damaged by the disease.
Reversing this nuclear 鈥渓eakiness鈥� could lead to new treatments for Parkinson鈥檚 and other neurodegenerative diseases 鈥� as well as reversing the effects of ageing more generally.
Opening door
The barrier between nucleus and cytoplasm is usually controlled by cellular gateways called nuclear pores. These are composed of complexes of 30 different proteins and regulate the passage of molecules in and out of the nucleus.
Hetzer and his colleagues wondered what happened to these protein complexes as cells age. 鈥淭he question was, [are they replaced] in non-dividing cells, or do they remain in place for the life of the cell?鈥� says Hetzer.
Using Caenorhabditis elegans, a roundworm that consists entirely of non-dividing cells as an adult, they showed that the proteins that make up the central scaffold of nuclear pores remain in place for the life of the cell. The same was true in non-dividing rat neurons.
The team also showed that this scaffold begins to break down in ageing cells as a result of oxidative stress, which allows other cell proteins to start invading the nucleus.
Plugged pores
鈥淲e think that the age-dependent deterioration of pores might be an ageing mechanism that leads to defects in nuclear function,鈥� says Hetzer. 鈥淲e are now investigating the possibility of plugging the leaky pores and thereby preventing the breakdown of cell compartmentalisation.鈥�
鈥淭his is a very important analysis of intracellular proteins that may undergo little or no turnover in non-dividing cells,鈥� says Aubrey de Grey of the , which promotes research into lifespan extension (see an interview with de Grey here).
However, he believes more research is needed to confirm that these key scaffold proteins remain in place once they have been damaged by oxidative stress. If they do not get replaced, 鈥渢his type of damage may need to be tackled as a component of any comprehensive intervention against ageing,鈥� he says.
Journal reference:
