Precision medicine developed to protect against intellectual disability during neurodevelopment.


Scientists from the The Scripps Research Institute (TSRI) have produced an approach that protects animal models against a type of genetic disruption that causes intellectual disability, including serious memory impairments and altered anxiety levels.  The findings focus on treating the effects of mutations to a gene known as Syngap1.  The team hope that these studies will eventually lead to a therapy specifically designed for patients with psychiatric disorders caused by damaging Syngap1 mutations, adding that the model shows that the early developmental period is the critical time to treat this type of genetic disorder.

Damaging mutations in Syngap1 that reduce the number of functional proteins are one of the most common causes of sporadic intellectual disability and are associated with schizophrenia and autism spectrum disorder. Early estimates suggest that these non-inherited genetic mutations account for two to eight percent of these intellectual disability cases. Sporadic intellectual disability affects approximately one percent of the worldwide population, suggesting that tens of thousands of individuals with intellectual disability may carry damaging Syngap1 mutations without knowing it.

In the current study, the researchers examined the effect of damaging Syngap1 mutations during development and found that the mutations disrupt a critical period of neuronal growth, a period between the first and third postnatal weeks in mouse models.  The team found that a certain type of cortical neuron grows too quickly in early development, which then leads to the premature formation of certain types of neural circuits.

The researchers reasoned that this process might cause permanent errors in brain connectivity and that they might be able to head off these effects by enhancing the Syngap1 protein in the newborn mutant mice. Indeed, they found that a subset of neurons were misconnected in the adult mutant mice, suggesting that early growth of neurons can lead to life-long neural circuit connectivity problems.

Then, using advanced genetic techniques to raise Syngap1 protein levels in newborn mutant mice, the researchers found this strategy completely protected the mice only when the approach was started before this critical developmental window opened.

As a result of these studies, the researchers are now developing a drug-screening program to look for drug-like compounds that could restore levels of Syngap1 protein in defective neurons. They hope that, as precision medicine advances, such a therapy could ultimately be tailored to patients based on their genotype.

Source:  The Scripps Research Institute (TSRI)

 

Synaptic proteins implicated in neurodevelopmental and neuropsychiatric disorders. A schematic illustration of an ensemble of pre- and post-synaptic proteins. The majority of these proteins are highly conserved across species, and thought to confer susceptibility to a host of neurodevelopmental and neuropsychiatric disorders including ASD. The cellular machinery of synapses is comprised of transmembrane heterophilic (such as Neurexin and Neuroligin) and homophilic cell-adhesion molecules (such as Cadherins and NCAM), cytoplasmic scaffolding proteins (such as PSD-95, Cask, and Shank) and cytoskeletal proteins (such as Homer and Cortactin) that link transmembrane and membrane-associated protein complexes with the underlying actin cytoskeleton. One of the emerging models in ASD is based on synaptic dysfunction in a molecular pathway that is orchestrated by trans-synaptic Neurexin–Neuroligin-dependent proteins complexes. This molecular assembly aligns the pre- and post-synaptic apparatus facilitating functional activation and modulation of ion channels that are in proximity to the neurotransmitter containing synaptic vesicles on the pre-synaptic side. These protein complexes recruit other proteins both pre- and post-synaptically and help organize functional neural networks. The cytoskeletal scaffolding protein Cask is one such notable protein which binds to the C-terminus of Neurexin. At the post-synaptic density, Neuroligin binds to PSD-95, other molecules such as PSD-93, SAP97, and the SAPAP family of proteins as well as the Shank family of scaffolding proteins help orchestrate the post-synaptic area. Homer and Shank function is thought to stabilize the post-synaptic density and serve as a platform to incorporate the post-synaptic receptors (such as NMDAR, AMPAR, and mGluR) into the machinery. The synaptic dysfunction in ASD may occur at multiple levels whereby failure to organize proper protein–protein interactions at the synapse may compromise neuronal functions.  Genetic aspects of autism spectrum disorders: insights from animal models.  Bhat et al 2014.

Synaptic proteins implicated in neurodevelopmental and neuropsychiatric disorders. A schematic illustration of an ensemble of pre- and post-synaptic proteins. The majority of these proteins are highly conserved across species, and thought to confer susceptibility to a host of neurodevelopmental and neuropsychiatric disorders including ASD. The cellular machinery of synapses is comprised of transmembrane heterophilic (such as Neurexin and Neuroligin) and homophilic cell-adhesion molecules (such as Cadherins and NCAM), cytoplasmic scaffolding proteins (such as PSD-95, Cask, and Shank) and cytoskeletal proteins (such as Homer and Cortactin) that link transmembrane and membrane-associated protein complexes with the underlying actin cytoskeleton. One of the emerging models in ASD is based on synaptic dysfunction in a molecular pathway that is orchestrated by trans-synaptic Neurexin–Neuroligin-dependent proteins complexes. This molecular assembly aligns the pre- and post-synaptic apparatus facilitating functional activation and modulation of ion channels that are in proximity to the neurotransmitter containing synaptic vesicles on the pre-synaptic side. These protein complexes recruit other proteins both pre- and post-synaptically and help organize functional neural networks. The cytoskeletal scaffolding protein Cask is one such notable protein which binds to the C-terminus of Neurexin. At the post-synaptic density, Neuroligin binds to PSD-95, other molecules such as PSD-93, SAP97, and the SAPAP family of proteins as well as the Shank family of scaffolding proteins help orchestrate the post-synaptic area. Homer and Shank function is thought to stabilize the post-synaptic density and serve as a platform to incorporate the post-synaptic receptors (such as NMDAR, AMPAR, and mGluR) into the machinery. The synaptic dysfunction in ASD may occur at multiple levels whereby failure to organize proper protein–protein interactions at the synapse may compromise neuronal functions. Genetic aspects of autism spectrum disorders: insights from animal models. Bhat et al 2014.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s