In a series of experiments on mice, the MIT investigators showed that they could undo the brain damage seen in a condition called Fragile X syndrome by inhibiting a key brain chemical called PAK.
In humans, Fragile X syndrome (FXS) is the leading cause of mental retardation and the most common genetic cause of autism -- the complex and devastating developmental disorder that is now being diagnosed in increasing numbers of children.
The study raises the intriguing possibility that the brain damage seen in children with the condition can be rolled back and identifies a specific target for potential drug therapies.
"It opens up a new avenue for drug research to treat this condition," said Susumu Tonegawa, a neuroscientist at the Massachusetts Institute of Technology in Cambridge, Massachusetts, and lead author of the paper.
MIT researchers began by creating a batch of mice that had been genetically modified to have Fragile X, a condition in which the neurons of the brain are structurally abnormal and functionally impaired compared to regular nerve cells.
These transgenic mice had many of the behavioral problems seen in kids with the condition: hyperactivity, attention deficits, repetitive behaviors and poor social skills.
The investigators then cross-bred these mice with another batch of mice that had been genetically modified to inhibit the activity of the PAK (p21-activated kinase) enzyme which is instrumental in shaping the formation of neuronal connections in the brain.
The researchers knew that when PAK was inactivated, the mice developed neurons that had short, fat dendritic spines, with a higher-than-usual capacity for relaying the electrical impulses that pass between brain cells.
In other words, the shape and function of the dendritic spines in the PAK mice was just the reverse of those seen in the brain cells of the mice with Fragile X syndrome.
The researchers gambled that the two abnormalities would cancel each other out, and that's exactly what the experiment showed.
The cross-bred mice had been genetically engineered so that the inactivation of the PAK enzyme began two weeks into the mouse's life cycle, which in human terms would be several years after birth.
Tests and autopsies showed that the PAK-blocking action restored electrical communication between neurons in the brains of the double mutant mice, correcting their behavioral abnormalities in the process.
"This is very exciting because it suggests that PAK inhibitors could be used for therapeutic purposes to reverse already established mental impairments in fragile X children," said Eric Klann, a professor at New York University's Center for Neural Science.
The study was conducted by Tonegawa and a postdoctoral student at MIT's Picower Institute for Learning and Memory and appears in this week's edition of the Proceedings of the National Academy of Sciences.
3 comments:
This seems like a huge breakthrough - is it possible that this could be related to the observed correction in symptoms when autistic children experience fevers (such as this article states)?
It seems that, (per this study) that the act of fever involves the "synthesis of hypothalamic protein with a rapid turnover". Perhaps the effort of the brain to produce cycloheximide and other proteins associated with fever leads it to repress its production of the PAK enzyme?
In doing some additional research on the PAK enzyme, I also came across this study which suggests that PAK deficits are responsible for both mental retardation and Alheizmers. While at first, this may seems contradictory to the analysis that an over-abundance of PAK enzyme would be a root cause of Autism, it begins to make sense if you think about the differences between autistic and mentally retarded children. Autistic kids almost seem like they're caught in a memory loop - constant repetition, obsessive behaviors - as if their brain will not let go of it's hold on their actions. While my experience with sufferers of Alheizmer's and mental retardation is limited, it almost seems like the opposite is true.
Could the root of both disorders be a lack of homeostatic generation of the same enzyme? I.e. it's not a matter so much of more PAK = good or bad, but rather that a functioning brain needs a balance to adequately. I note that in the article, they suggest that the use of PAK inhibitors could reverse the trend of autism, but it's evident from the that PAK is also necessary for appropriate brain function (per the Alzheimer's study). As such, it would require some pretty significant testing to ensure that correct dosages of the PAK inhibitor were administered and maintained. Additionally, the study did not cite the effects of removing the PAK inhibitor after the mice had regained normal brain function.
Would this mean that human autistics would be regulated to a regimen of medication similar to diabetics, with the risk of mental retardation in the case of an overdose? Or is there a way to actually correct the brain's regulation of PAK enzymes to ensure proper function? My suspicion is that this would be much harder to do, but nonetheless, this study brings some real hope to finding and curing autism.
Hey, any more info on this, e.g. possibilties of human trials, future treatments, that kind of stuff?
Thanks.
-nycaspy
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