Aging And Angelman Syndrome — Is There A Link?

June 27, 2010

Is there a link between aging of the brain and the neural defect that underlies Angelman Syndrome?  A new study suggests the answer is yes.   A surprising result that may help the development of new treatments to improve outcomes for children with Angelman Syndrome and encourage healthy aging.

Ubiquitin PathwayAngelman syndrome is a severe neurodevelopmental disorder that is caused by a mutation in the UBE3A gene.  This affects the production of the E3 ubiquitin ligase, an enzyme that selectively marks proteins for degradation.  A balance between synaptic proteins and their degradation is essential for normal neural transmission and plasticity.  When the Ube3A enzyme is not made in the brain it causes a loss of synaptic plasticity and this loss is accelerated by simply using the synapses.   A study published last year in Nature Neuroscience (Yashiro et al., 2009) showed that synapses in the cortex of Ube3A knockout mice become rigid and do not function normally.

This description of rigid synapses and loss of plasticity lead my research group (Williams et al., 2010) to ask if a loss of Ube3A is part of normal aging.   Abnormal ubiquitinated proteins are characteristic of many neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease.  Furthermore, longevity studies have shown that Ube3A is necessary for a caloric restriction diet to increase lifespan.  So what happens during normal aging?

We found that both animal and human brains lose Ube3A across the lifespan.  But the loss in human brains is different.  During aging of the human brain there is a greater loss of Ube3A than other synaptic proteins.  This points to a specific vulnerability in the aging human human brain that may lead to rigid synapses, loss of plasticity, and decline of cognitive function.

There is, however, a key difference between between the Angelman mice and human aging.  In  Angelman mice plasticity is preserved by restricting experience.  But the best way to preserve function during normal aging is to engage in activities that keep the mind and body active.  Clearly, the loss of Ube3A during aging of the human brain must be more complicated that just losing Ube3A at all synapse.  This raises the intriguing possibility that Ube3A is lost at some synapses and not others during aging.

It will be important to determine what drives the loss of Ube3A during aging of the human brain and if certain circuits are more vulnerable than others.  But perhaps more pressing is to figure out if the loss can be prevented.  Encouraging results from a recent study (Greer et al., 2010) show that enriched experience in adult mice increases Ube3A expression in an important memory center in the brain (hippocampus).

So keep trying new things and expanding your range of experiences.  Who knows it just might help the Ube3A in your brain.

Dramatic loss of Ube3A expression during aging of the mammalian cortex
Kate Williams 1, David A . Irwin 1, David G . Jones 1 and Kathryn M. Murphy 1, 2*
1 McMaster Integrative Neuroscience Discovery and Study Program, McMaster University, Canada
2 Psychology, Neuroscience&Behaviour, McMaster University, Canada

Greer, P. L., Hanayama, R., Bloodgood, B. L., Mardinly, A. R., Lipton, D. M., Flavell, S. W., Kim, T. K., Griffith, E. C., Waldon, Z., Maehr, R., Ploegh, H. L., Chowdbury, S., Worley, P. F., Steen, J., and Greenberg, M. E. (2010). The Angelman Syndrome protein Ube3a regulates synapse development by ubiquitinating arc. Cell 140, 704–716.

Yashiro, K., Riday, T., Condon, K., Roberts, A., Bernardo, D., Prakash, R., Weinberg, R., Ehlers, M., and Philpot, B. (2009). Ube3A is required for experience-dependent maturation of the neocortex. Nat. Neurosci. 12, 777–783.


Fantastic Voyage here we come — Nanoscale imaging of the living brain.

September 9, 2009

Once again neuroscientists and physicists have teamed up to take brain imaging to a new level — Supraresolution imaging.  This has the making of a great SciFi movie — A team of researchers at Harvard University, led by Dr Bernardo Sabatini, combine laser imaging techniques, two-photon laser scanning microscopy (2PLSM) and continuous wave stimulated emission depletion (STED), to go where no human has gone before, peering deep into living brain slices to see nanoscale features of functioning neurons.neuron_63_4

Ok, so they did not use the lasers to shrink themselves like Fantastic Voyage or Honey I Shrank the Kids, but it is still really cool.

Using 2PLSM&STEM imaging Sabatini’s team showed that they can see features as small as 100nm deep in living brain tissue.  This is about 3 times better than just 2PLSM imaging.   How good is supraresolution imaging with STED&2PLSM?  It is the ability to see features of living neurons that are 2000-5000 thinner than a human hair.  Features like the shape of small spines on neuronal dendrites, proteins in a neuron, ion channels at a synapse, and biochemical microdomains in a dendrite. Read the rest of this entry »


Neuroscientists have discovered a clue to what is hidden behind the smiling face of a child with Angelman Syndrome.

June 4, 2009

poster-child001Children with Angelman Syndrome develop normally until about 1 year of age and then their intellectual development stops. They fail to develop language and other cognitive skills, are severely mentally handicapped, but have a happy disposition, laughing, smiling and enjoying social interaction. What could be behind this syndrome?

A new study of Angelman Syndrome shows that an interaction between the genetic defect and sensory activity robs cortical synapses of their normal plasticity. Simply using the synapses depletes them of plasticity. This leaves neural connections in the cortex rigid, unable to be fine tuned and to develop normal function.
Read the rest of this entry »


This is your brain on art!

May 14, 2009

Have you ever thought about what’s going on in your brain when you look at a painting that you like a lot? While Neuroscientist Dr. Edward Vessel has and he’s done brain imaging experiments to figure it out.

What happens in your brain when you have a pleasurable experience — for example, when you see at a painting that you like very much. Scientists describe this as an aesthetically pleasing experience. They want to know if simply seeing a painting that you enjoy engages an emotional response and triggers the emotion circuits in your brain.
Read the rest of this entry »


Neuroscientists decode brain activity important for navigation and spatial memory

April 29, 2009

How many times have you wondered where did I leave my keys?  Activity in your hippocampus and medial temporal lobes encodes the answer.

A new study using high resolution brain imaging has shown that the encoding of memories involves the precise pattern of activity of a very large number of neurons in the human hippocampus.  The hippocampus and surround medial temporal lobes are important parts of the brain for our ability to navigate, form and recall memories, and imagine future experience.  This study found that the pattern of activity can be read like a map to accurately “predict” what environment you are in and your location within the environment.

A group of Neuroscientists at the Welcome Trust Centre for Neuroimaging at University College London led by Dr. Eleanor Maguire have imaged the pattern of activity in the hippocampus and surrounding medial temporal lobe of human subjects while they navigated around a virtual environment.  The researchers asked if there is a reliable pattern of activity in the hippocampus, like a map, that can be read to predict where the subject is in the environment.   The results of this study are “yes” — there is a functional structure to the pattern of activity in the human hippocampus that encodes your location in an environment.
Read the rest of this entry »


Mirror neurons reflect more than understanding

April 19, 2009

This blog entry is about one of the most interesting discoveries of the 90’s in Neuroscience — Mirror Neurons — and a recent research paper that adds to their intrigue.  Mirror neurons are found in the premotor cortex, and what has made them so interesting is that they fire both when the individual performs a goal-directed action and when they watch someone else perform the same action.  It is as if the mirror neurons encode an understanding about the intentions of someone else.  For example, when my husband reaches for his coffee cup I understand that he intends to take a drink before he even raises the cup to his lips.  Neuroscientists think it is the mirror neurons that encode the “understanding” when we watch what others are doing.

A recent study suggests that mirror neurons may do more than just reflect understanding others.  A group of Neuroscientists in Tubingen Germany and Parma Italy has shown that mirror neurons may contribute to thinking about how to interact.
Read the rest of this entry »


Neural Stem Cells in the Aged Brain

April 12, 2009

Within the last 20 years neuroscientists have shown that new neurons are generated in the brain throughout the lifespan. This finding opened a new area of research aimed at understanding if adult neural stem cells can be used in therapies for neurodegenerative diseases.

A challenge with this approach is that there are fewer neural stem cell in the aged brain and the loss of stem cells occurs at just the time when neurodegenerative diseases are most common. But a new study is providing important information that neural stem from an aged brain still have the capacity to mature into functional neurons.
Read the rest of this entry »