New previously unseen cellular mechanism identified in Fragile X syndrome.


Fragile X syndrome, an inherited cause of autism and intellectual disability, can have consequences even for carriers of the disorder who don’t have full-blown symptoms.  Some carriers may experience social deficits and milder versions of cognitive and behavioral disorders associated with full-blown fragile X syndrome. These include autism spectrum, attention deficit hyperactivity, and mood and anxiety disorders.

Now, researchers at Washington University School of Medicine have identified a potential target for treatments for fragile X carriers. This population includes 1 million women and 320,000 men in the United States, according to a 2012 study led by the Centers for Disease Control and Prevention.

The team state that full-blown fragile X syndrome eliminates the body’s ability to make a key brain protein.  In contrast, carriers of the mutation make the protein but produce significantly less of it than people without the mutation. The current study has identified a potential way to boost levels of this protein. This ultimately could lead to treatments to ease the carriers’ symptoms.  The opensource study is published in the journal Neuron.

The distinction between being a carrier and having full-blown fragile X hinges on the nature of a mutation in the FMR1 gene, explain the team, adding that the mutation occurs when a portion of the genetic code is repeated erroneously. The protein made by the gene is known as the fragile X mental retardation protein.  Previous studies have shown that if the erroneous repeat of genetic code occurs more than 200 times, it blocks the body from making the fragile X mental retardation protein and causes the full-blown condition, which can impair brain development. This can lead to intellectual and attention deficits, which can be severe, as well as hyperactivity, social anxiety and other problems.  Carriers have versions of the gene with fewer erroneous repeats in the FMR1 gene and develop more subtle symptoms.

The team was studying an enzyme known as Cdh1-APC when several clues suggested it might be linked to the fragile X protein. They investigated Cdh1-APC because of its role in shaping the growth and structure of nerve cells.  Cdh1-APC binds to other proteins in the brain to target them for disposal in a dynamic fashion when their services are no longer needed, state the team.  The researchers have shown that Cdh1-APC’s ability to do this is important to the development and structure of brain cell networks, however, the lab also are interested in how it affects synapses, or the connections where nerve cells communicate with each other.

The team knocked out Cdh1-APC in mice and then looked at a single, well-studied synapse between a pair of nerve cells in the hippocampus, a structure of the brain that is important for learning and memory. They found that an adjustment of the signaling process across synapses was changed.  The team explain that nerve cells use a phenomenon called plasticity to encode memory by altering the ease with which they send signals to each other.  One form of plasticity is called long-term depression. At the synapse the researchers studied in the hippocampus, this form of plasticity was disabled when they knocked out Cdh1-APC.

Previous studies have shown that the loss of the fragile X mental retardation protein is also linked to alterations in the form of plasticity called long-term depression. It is linked in a way that suggests that Cdh1-APC might act on the fragile X mental retardation protein. Based on this and other clues, the team identified a segment in the fragile X protein where Cdh1-APC binds and marks it for degradation. The current study showed in experiments in cells and in the mouse brain that the two proteins interact in this fashion.

The team hypothesize that if they can find a way to block the interaction between Cdh1-APC and the fragile X mental retardation protein or to block the ability of Cdh1-APC to cause degradation of the protein, that should make more of the fragile X protein available in the brain and reduce some of the symptoms experienced by carriers of this disorder.

Source:  Washington University School of Medicine 

 

Cdh1-APC Operates in the Cytoplasm Rather Than the Nucleus to Regulate mGluR-LTD.  E15 mouse embryos electroporated with a plasmid expressing GFP-NES-Cdh1 (a–d) or GFP-NLS-Cdh1 (e–h) together with an mCherry-expressing plasmid were allowed to develop until P20. Brain sections were subjected to immuno-fluorescence analyses with GFP and DsRed antibodies and the DNA dye bisbenzimide (Hoechst 33258).  GFP-NES-Cdh1  and  GFP-NLS-Cdh1 appeared to be predominantly in the cytoplasm and nucleus, respectively. Areas inside the white boxes (a–h) are enlarged (a0–h0). Scale bars represent 100mm. Notably, although GFP-NLS-Cdh1 displayed modest expression in the soma in addition to robust expression in the nucleus, GFP-NES-Cdh1 was restricted to the cytoplasm and excluded from the nucleus in CA1 neurons.  A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain.  Bonni et al 2015.

Cdh1-APC Operates in the Cytoplasm Rather Than the Nucleus to Regulate mGluR-LTD. E15 mouse embryos electroporated with a plasmid expressing GFP-NES-Cdh1 (a–d) or GFP-NLS-Cdh1 (e–h) together with an mCherry-expressing plasmid were allowed to develop until P20. Brain sections were subjected to immuno-fluorescence analyses with GFP and DsRed antibodies and the DNA dye bisbenzimide (Hoechst 33258). GFP-NES-Cdh1 and GFP-NLS-Cdh1
appeared to be predominantly in the cytoplasm and nucleus, respectively. Areas inside the white boxes (a–h) are enlarged (a0–h0). Scale bars represent 100mm. Notably, although GFP-NLS-Cdh1 displayed modest expression in the soma in addition to robust expression in the nucleus, GFP-NES-Cdh1 was restricted to the cytoplasm and excluded from the nucleus in CA1 neurons. A Cdh1-APC/FMRP Ubiquitin Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian Brain. Bonni et al 2015.

 

 

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