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Research Summary

Synapses are specialized cell-cell contacts that mediate the flow of information though the neural circuits in our brains. Synaptic dysfunction predispose to neurodevelopmental and psychiatric disorders such as autism and schizophrenia. Synapse pathology and loss are also hallmark features of common neurodegenerative conditions including Alzheimer’s disease and Parkinson’s disease.

Formation and maturation of synaptic connections are thought to depend on interactions between neuronal adhesion proteins that span the synaptic cleft to form a physical bridge between contacting neurons. Such interactions may not only ensure correct connectivity, but also serve to specify the properties of specific synapses, for example to ensure correct matching of presynaptic neurotransmitter type with appropriate postsynaptic receptors. Pre-synaptic neurexins constitute a well-established family of synaptic adhesion proteins, which interactions with diverse post-synaptic partners shape the properties of synapses by defining their molecular architecture. Mutations in the gene for neurexin-1 have repeatedly been found to confer genetic risk for autism and schizophrenia.

We are interested in understanding how these protein-protein interactions contribute to sculpt specific synaptic connections in our brains. More specifically, we are interested in the post-translational regulation and intracellular signaling of synaptic adhesion molecules:

(1) Understand the function of carbonic anhydrase-related proteins and their possible role in regulating synaptic cell-adhesion complexes.

We have found that two carbonic anhydrase-related proteins, CA10 and CA11, which have an unknown function in the cell, can interact with neurexins (Sterky et al., PNAS 2017). At least under some circumstances, this binding can regulate the synaptic levels of neurexins. Yet, the role of these proteins and their interactions with neurexins in the mammalian brain remains unknown. We will address these questions by a combination of mouse genetics, proteomics and protein biochemistry. This project serves to reveal the function of two conserved proteins in our brains and also provide a means to understand the post-translational regulation of the neurexin-complex.

(2) Study mechanisms of synapse development in a reduced in vitro system.

In addition to neurexins, several other families of cell surface receptors have the ability to induce pre- or postsynapse formation on contacting neurons. While it is generally believed that clustering of these receptors at contact sites cause recruitment of intracellular scaffold proteins that assemble additional synaptic components, the intracellular pathways and signals that links receptor binding to synapse formation are not well understood. We will study these pathways by protein biochemistry and simplified cell-based assays.

(3) Study the role of patient-specific mutations by genetic disease modeling in human neurons.

Next-generation sequencing technologies (e.g. whole-exome or -genome sequencing) have revolutionized the diagnostics of rare genetic disease. Yet, pinpointing the causative mutations in this wealth of resulting data is sometimes challenging. Computer algorithms often fail to reliably predict if a mutation that has not previously been studied can impair cellular functions to cause disease and experimental studies of the candidate mutation are often needed.

Building on the experience of working with pluripotent cells (ESCs or IPSCs) at the Department of Clinical Chemistry, we will use CRISPR/Cas9 gene editing to create reverse genetic disease models. To study the role of the specific mutation in human neurons, we use a rapid and efficient protocol for direct lineage-conversion (see Zhang et al., Neuron 2013, 78: 785–798). In combination, these methodologies will allow us to study disease mechanisms in children with unclear neurodevelopmental conditions. For example, we aim to identify processes whereby cell-autonomous metabolic defects could cause synaptic dysfunction and give rise to neuropsychiatric symptoms.
 

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Page Manager: Mattias Lindgren|Last update: 12/12/2017
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