Role of LGI and ADAM proteins in the functional organization of the myelinated axon
Lead Research Organisation:
University of Edinburgh
Department Name: Biomedical Sciences
Abstract
Voltage-gated ion channels shape the physiological properties of neurons. Their vital role in normal nervous system function not only depends on their intrinsic biophysical properties but also on their surface density and cellular distribution. This PhD project is part of a larger research programme that aims to determine how ion channel surface density and cellular distribution is regulated and is founded on our discovery that the high-density accumulation of shaker type voltage-gated potassium channels (Kv1) at specific axonal domains critically depends on members of a small family of secreted proteins and their receptors (Leucine-rich Glioma-Inactivated, LGI and A Disintegrin And Metalloprotease, ADAM families respectively). Mutations or autoimmune disease affecting shaker type potassium channels, LGI and ADAM proteins are associated with epilepsy, ataxia and encephalitis, but the functional interactions between these proteins remain poorly understood.
Through the use of super resolution light microscopy and 3D electron microscopy we will explore the cellular distribution of Kv1 channels, Adam23/22 and its ligands Lgi2 and Lgi3 in myelinated axons of the developing peripheral and central nervous system of wildtype and Lgi3/2 and Adam23 mutant mice. In addition, we will study the interaction between Kv1 and Adam23/Lgi3 by a novel biotinylation technology, immune-precipitation, Western blotting and mass spectrometry to reveal the mechanism through which Lgi proteins direct the correct targeting and assembly of Kv1 protein complexes. Furthermore, we will establish how the specific localization of Kv1 channel clusters contributes to the electro-physiological properties of myelinated axons.
Through the use of super resolution light microscopy and 3D electron microscopy we will explore the cellular distribution of Kv1 channels, Adam23/22 and its ligands Lgi2 and Lgi3 in myelinated axons of the developing peripheral and central nervous system of wildtype and Lgi3/2 and Adam23 mutant mice. In addition, we will study the interaction between Kv1 and Adam23/Lgi3 by a novel biotinylation technology, immune-precipitation, Western blotting and mass spectrometry to reveal the mechanism through which Lgi proteins direct the correct targeting and assembly of Kv1 protein complexes. Furthermore, we will establish how the specific localization of Kv1 channel clusters contributes to the electro-physiological properties of myelinated axons.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M010996/1 | 01/10/2015 | 31/03/2024 | |||
| 1952685 | Studentship | BB/M010996/1 | 01/10/2017 | 30/09/2021 |
| Description | The ability of nerve cells (neurons) to process information relies on distinct properties and precise distribution of ion channels in the nervous system. Dysfunctional or mislocalized ion channels can lead to a wide range of diseases including epilepsy, chronic pain, ataxia and neuropathy, all characterized by improper neuronal conduction. In the Meijer lab, our work revolves around a specific family of ion channel - voltage-gated potassium channels 1 (Kv1). Using genetic manipulation in mouse models as well as in-vitro, cell culture-based experiments, we identified several molecules associated with Kv1 channel complexes. We can now show that these molecules - Lgi2, Lgi3 and Adam23 - interact with each other to ensure proper localization of Kv1 channels in the nervous system and therefore facilitate healthy neuronal conduction. |
| Exploitation Route | The outcomes of this funding are likely to be used by other scientists in directing their own research in the field of neuronal excitability. If taken further, our findings could could be used in medical targeting of peripheral neuropathies. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Translator for Eurostemcell.org |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | As a volunteering translator at Eurostemcell.org, I regularly review and translate stem cell-related articles from English to Polish. My work allows lay audiences for whom English is not the first language, to have access, understand and keep up to date with the progress in stem cell research. |
| Year(s) Of Engagement Activity | 2018,2019,2020 |
| URL | https://www.eurostemcell.org/ |
| Description | Volunteer at MRC Festival of Science |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | I participated in the 'World of Science' event organised by Scottish Centre for Regenerative Medicine (SCRM) Community Engagement team as part of MRC Festival of Science. The event, which took place at Craigmillar Library, celebrated the diversity of scientific and local communities. Our research demonstrations and hands-on activities allowed local school children and residents to engage with global medical research - in their first language - and understand how the work of the MRC and CRM fits into that. |
| Year(s) Of Engagement Activity | 2019 |