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Fredrik Sterky Group

Fredrik is a resident physician in Clinical chemistry with research time within Wallenberg Centre. He is interested in how our brains normally develop and function, and how mutations in specific genes can impair these processes and cause human disease.

Our current focus serves to:

(1) Understand the function of carbonic anhydrase-related proteins and their role in regulating a synaptic cell-adhesion complex linked to autism.

Our everyday thoughts and actions are mediated by the flow of information across synaptic connections. Synaptic dysfunction is associated with neurodevelopmental and psychiatric disease as well as several neurodegenerative conditions. The formation and specification of synaptic connections are at least in part mediated by interactions between cell-adhesion molecules, which span the synaptic cleft to form a physical interaction between the presynaptic and the postsynaptic neurons. Neurexins constitute a family of such pre-synaptic cell adhesion receptors that interact with diverse ligands on the postsynaptic neuron to influence the molecular architecture of the synapse. Truncating mutations in the Neurexin-1 gene have repeatedly been associated with ASD and risk of developing schizophrenia, but how reduced levels of neurexins cause human disease is not well understood.

We have found that two carbonic anhydrase-related proteins, CA10 and CA11, which have an unknown function in the cell, can interact with neurexins in an unconventional manner (Sterky et al., PNAS 2017). At least under some circumstances, their binding increases 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 and protein biochemistry. This project serves to reveal the function of two conserved proteins in our brains and also provide a means to understand how the neurexin-complex is normally regulated.

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

Next-generation sequencing technologies (e.g. whole-exome or -genome sequencing) are revolutionizing the diagnostics of rare genetic disease. Instead of focusing on one candidate gene at a time, these methods can analyze most of our ~20 000 genes at once. However, pinpointing the causative mutations in this wealth of data remains a major challenge. Computer algorithms that filter and interpret candidate mutations are improving, but often fail to reliably predict if a mutation that has not been studied previously will impair cellular functions to cause disease. Experimental studies of the candidate mutation is often needed to obtain a more definitive diagnosis and can also provide insights into disease mechanisms.

At the Department of Clinical Chemistry at the Sahlgrenska University Hospital, we diagnose of children with suspicion of mitochondrial disease and other inborn errors of metabolisms (IEMs). We regularly identify new candidate disease-causing mutations and sometimes mutations in genes not previously linked to human disease. In these cases, patient-derived fibroblasts have traditionally been used for complimentary experimental studies. However, the use of fibroblasts has disadvantages: First, the patient-derived cells will not only carry the candidate mutation but also all other genetic variants that differs between the patient and non-affected controls. In addition, fibroblasts (a type of cell derived from the skin) may not be representative for studying disease mechanisms specifically affecting the nervous system. We therefore aim to develop an alternative approach whereby the candidate mutation found in the patient is introduced into human cells derived from a healthy individual. We are currently working with resources available at the clinic to implement and refine CRISPR/Cas9 gene editing methods to this aim. By using pluripotent cells (ESCs or IPSCs) the resulting cells can rapidly be differentiated into human neurons by a recently developed protocol (Zhang et al., Neuron 2013), which will allow us to study disease mechanisms in children with developmental delay and neurological symptoms.

We Are Seeking Outstanding Researchers

Contact Information

Fredrik Sterky

fredrik.sterky@gu.se

 

Page Manager: Pontus Sundén|Last update: 5/12/2017
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Denna text är utskriven från följande webbsida:
http://wcmtm.gu.se/research-groups/sterky/
Utskriftsdatum: 2017-11-21