"Our major discovery is that presenilin has a novel role, which is to control the movement of motor proteins along neuronal highways," said Gunawardena, an assistant professor of biological sciences. "If this regulation/control is lost, then things can go wrong. This is the first time a protein that functions as a controller of motors has been reported.
"In Alzheimer's disease, transport defects occur well before symptoms, such as cell death and amyloid plaques, are seen in post-mortem brains," she added. "As a result, developing therapeutics targeted to defects in neuronal transport would be a useful way to attack the problem early."
To see a video of traffic flowing normally in a fruit fly larval nerve, visit http://www.youtube.com/watch?v=sWTKZwHwdBg
The findings are particularly intriguing because scientists have known for several years that presenilin is involved in Alzheimer's disease.
Presenilin rides along neuronal highways in tiny organic bubbles called vesicles that sit atop the kinesin and dynein motors, and also contain a second protein called the amyloid precursor protein (APP). Presenilin participates in cutting APP into pieces called amyloid beta, which build up to form amyloid plaques in patients with Alzheimer's disease.
Such buildups can lead to cell death by preventing the transport of essential materials—like proteins needed for cell repair—along neurons.
The findings of the new study mean that presenilin may contribute to Alzheimer's disease in at least two ways: not just by cleaving APP, but also by regulating the speed of the molecular motors that carry APP along neuronal highways.
"More than 150 mutations in presenilin have been identified in Alzheimer's disease," Gunawardena said. "Thus, understanding its function is important to understanding what goes wrong in Alzheimer's disease."
To track the movement of the kinesins and dyneins, the team tagged their cargo with a yellow fluorescent protein. This enabled the scientists to view the molecular motors chugging along inside the neuron under a microscope in a living animal. A special computer program then analyzed the motors' paths, revealing more details about the nature of their movement and how often they paused.
Kinesin and dynein motors carrying the Alzheimer's protein APP travel on microtubule tracks in a single axon in the nerve of a fruit fly larva. This video shows the motors' normal behavior; when the level of presenilin was reduced in a study, the motors increased their velocity.
(Photo Credit: Shermali Gunawardena)
Expression of human APP in fly larval nerves causes neuronal blockages (arrows, top panel) which are rescued by reductions in presenilin. Expression of human APP in fly larval brains causes cell death (arrows, bottom panel) which are rescued by reductions in presenilin.
(Photo Credit: Shermali Gunawardena)
Source: University at Buffalo