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Posts Tagged ‘PTEN’

New Findings on Sensory Overload: A First-Person Perspective

February 2, 2012 15 comments

Guest blog post from Autism Speaks Science Board Member John Elder Robison, author of Look Me in the Eye: My Life with Asperger’s and Be Different: Adventures of a Free-Range Aspergian

According to a press release I received this morning, new research from Cold Spring Harbor Lab might help explain how a gene mutation found in some autistic individuals leads to difficulties in processing auditory cues and paying spatial attention to sound. [Editor’s note: See our related science news story on this Autism Speaks-funded study.]

The study found that when a gene called PTEN is deleted from auditory cortical neurons—the main workhorses of the brain’s sound-processing center—the signals that these neurons receive from local as well as long-distance sources are strengthened beyond normal levels.  That’s the first interesting part of the study.

PTEN has been associated with autism in a number of previous studies. In particular, the PTEN variation has been found in autistic people with larger heads, and it’s suspected as a cause of both additional connectivity in the brain and additional brain cell growth.

How many of today’s autism population have a PTEN variation?  Do you?  No one knows.  It’s one of many genes researchers are studying.

What I do know is that I have abnormal sensitivity to sound, as do many autistic people. Many of us are easily overwhelmed by noises that go unremarked by the rest of the population. For some time, I have realized my excess sensitivity is a two-edged sword. On the one hand, it gave me powerful insight into music and facilitated my earlier career in rock and roll. On the other hand, it has often put me at a disadvantage as I’m rendered inoperative by what others see as ordinary situations.

It’s interesting to read that PTEN may be a cause of that difference. Understanding the genetic foundation of why that happens doesn’t do me much good, but the next part of the study might:

Researchers found that those can be blocked by rapamycin, a drug currently in use as an immunosuppressant. Rapamycin as an autism therapy has been studied before and found beneficial in some cases. This study is one of the first that sheds light on “why” and speaks to a specific mechanism by which we may be disabled.

Now that I’ve come to know many people on the spectrum, I realize I am one of a fortunate few who have significant sensory sensitivity without being disabled by it.  The vast majority of autistic people who write about sensitivity do so in the context of disability. If there were a way to reduce sensory overload, I’m sure a number of folks on the spectrum today would like to hear about it.

One next step might be to see if rapamycin has the same effect in humans, and what other unforeseen effects it may have. Rapamycin has already been tried as a therapy in other contexts relating to autism. A targeted study that looked at the drug’s effect specifically on sensory overload would be very interesting.

It’s possible that this research illustrates a first step on the path to remediating a specific component of disability for many people on the spectrum. Much more testing will be needed to really know if that’s true, but it looks like a promising start.

My biggest concern is that rapamycin may have unforeseen effects elsewhere in the brain, and we won’t be able to understand that until we have conducted a sizeable human trial. We can only do so much by observing and extrapolating from mice.

An interesting aside is that Dr. Zador’s research further supports the emerging idea that excessive brain plasticity is a key component of the brain differences that lead to autism. His research premise is that the PTEN variation causes excess connectivity, and connectivity is a key element of plasticity. I’ve written about that idea in earlier posts.

I read a lot of talk in the autism community that questions why we spend money on genetic research when today’s autistic population needs help now. There is a popular perception that genetic research can only benefit unborn generations, or even worse, be used as a tool for selective abortion.

Dr. Zador’s study shows a clear pathway from a basic genetic study to a possible therapy for autistic people today, if they suffer sensory overload issues. It’s a perfect example of why this kind of work continues to be important and needs to be funded alongside all our other efforts in the autism research arena.

One of the pathways regulated by the PTEN protein involves shutting down an intracellular enzyme called mTORC1, which promotes cell growth, among other things…. While Zador is excited about “this finding that suggests that mTORC1 could be a good therapeutic target for some cases of PTEN-mediated brain disorders,” he is also keen to further pursue his team’s new evidence that cortical hyperconnectivity could be the “final pathway” by which diverse ASD genetic pathways lead to a single ASD phenotype. “Using cortical connectivity as a paradigm for assessing ASD candidate genes could provide insights into the mechanisms of the disorders and perhaps even give us clues to formulate new therapeutic strategies,” he states.

Dr. Zador’s leap from a subtle variation in genetic code to a specific behavioral aberration represents a brilliant leap of intuition and reason, backed up with careful lab work. It’s the kind of result I hope to see when I cast my vote for further genetic studies. This work was originally funded by Autism Speaks and NIH four years ago.

Here’s another really fascinating point to ponder. The PTEN genetic variation has been already associated with certain people with severe autistic disability and people with tubular sclerosis. Now, by associating PTEN with auditory sensitivity, we confront the question:  Do people like me have the PTEN difference too?  No one knows, because that study has never been done.

I’ll just say one more thing in closing. The discovery that PTEN aberrations can lead to sensory overload, and the pathway by which that happens stands separate from any question about rapamycin as a therapy. Don’t let worries about a particular drug blind you to the significance of the first finding.

Other researchers are looking at alternate ways to affect cortical plasticity in general and even connectivity as described in this study.  Rapamycin may end up being a therapeutic answer for some, but it’s equally possible that a better therapy will be developed now that we are beginning to unravel the underlying issues. One day, autistic people who are disabled by auditory overload may be able to “mute” the disability, while retaining enough sensitivity to be exceptional.

That, folks, is what the science is all about.

5|25: Celebrating Five Years of Autism Science Day 4: Convergence on PTEN Signaling Pathway

February 4, 2010 Leave a comment

In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our fourth item, Convergence on PTEN Signaling Pathway, is from Autism Speaks’ Top 10 Autism Research Events of 2007.

Model systems for studying the complex and fundamentally human challenge of autism will be vitally important to solving autism because they allow researchers to study the underlying biology in a manner that is not possible in humans. Finding an animal model system with similar behavioral tendencies as humans allows researchers to study which biochemical pathways break down in autism and, most importantly, how they can be treated. In 2007, researchers added an important new model system to their arsenal, the “PTEN conditional knockout” mouse.

PTEN is a gene that encodes for a protein involved in several critical signaling pathways inside cells, including metabolism, growth and survival. To carry out its cellular duties, PTEN interacts with several other important proteins in a biochemical signaling cascade. Other proteins in this signaling pathway have previously been tied to developmental disorders such as Tuberous Sclerosis and Neurofibromatosis. In 2005, researchers found that within a small subset of individuals with autism and macrocephaly (large heads) 17% had mutations in the PTEN gene. This raised the possibility that disrupting PTEN activity, and the signaling pathways within which it functions, may result in some forms of autism. This year researchers succeeded in using complex genetic manipulations to shutdown the mouse version of the gene (PTEN) in the brain of young mice. Surprisingly, not only did these animals grow larger brains, the mice also displayed abnormal social behaviors and seizures, both of which can be features of autism.

These results provided important data supporting the emerging relevance of cellular signaling pathways to autistic behaviors, and are now focusing some researchers on specific molecules that could potentially become targets for cell-based therapeutics.

Update since this story was first run: Having discovered that disrupting the PTEN signaling pathway leads to autism-associated signs, in 2009 the researchers went on to further show that manipulation of the PTEN signaling pathway can serve as a successful treatment strategy. Making use of these same mice, they found that treatment with a pharmacological inhibitor of the PTEN pathway improved the autism-like pathology of the animals, including unusual social behaviors and seizures. Published in the Journal of Neuroscience, the newest data strengthen the case for focusing on this signaling pathway as a viable target for novel autism therapeutics.

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