Our Research

Our research focuses on how to build and maintain a nervous system for life. We use C. elegans as a model system because we can use sophisticated genetic, imaging and molecular approaches to study the cellular mechanisms of neuroprotection in exquisite detail.

Neurons are subjected to continuous strain, mostly due to body movement and their location within skin, muscles, organs, and joints.  Excessive mechanical strain, or shear stress due to external or internal traumas, can trigger degeneration.  Virtually every neuron, including those of the central nervous system, is susceptible to different types of strain insults and mechanical strain has been implicated in the progression of neurodegenerative disease. The aim of the Coakley lab is to understand the molecular mechanisms that protect against motion-induced injury in order to ensure that neurons maintain their correct structure and function throughout life.

Axonal integrity is essential for nervous system function

Failure to maintain the integrity of the axon, the longest and most susceptible compartment of a neuron, results in compromised neuronal function, which is characteristic of both traumatic injury and neurodegenerative diseases. Virtually every neuron, including those of the central nervous system, is susceptible to different types of strain insults such as vascular accidents and trauma with excessive mechanical strain triggering axonal degeneration and the progression of neurodegenerative diseases. Understanding the molecular mechanisms that maintain axonal integrity is therefore essential for developing neuroprotective therapies for human disorders and injury.

The cytoskeletal spectrin network protects axons from damage

The cytoskeletal spectrin network is present in cells and regulates cellular architecture and mechanical stability. It is a characteristic feature of axons and, since first being revealed by super-resolution microscopy, its distinct periodic scaffold composed of α- and ß-Spectrin tetramers has been observed within axons of every neuronal subtype and species tested. The role of the spectrin network in stabilising axons against mechanical stress is also conserved and proposed to function intrinsically within neurons by providing spring-like elasticity, thus protecting them from axonal damage. Human mutations in ß-Spectrin are associated with several disorders, including spinocerebellar ataxia, a neurodegenerative disorder that is characterised by uncoordinated gait, limb and eye movement defects, slurred speech and swallowing difficulties. In the nematode C. elegans, mutations in unc-70/ß-Spectrin cause sensory and motor axons to become hyper-fragile and spontaneously break due to body movement.

Recently, we discovered that ß-Spectrin functions within the epidermis to maintain the structural integrity of sensory axons in C. elegans. This significant conceptual shift challenges decades of dogma that ß-Spectrin functions within neurons to preserve axonal integrity and instead proposes that ß-Spectrin functions extrinsically in the surrounding tissue to protect the axon. This innovative notion could have broad implications for the understanding and treatment of a wide range of human disorders caused by spectrin dysfunction and paves the way to an entirely new way of thinking about neuroprotection.

How does epidermal spectrin protect the neuron from damage? Do human homologues function in the same way? Are similar mechanisms present in other non-neuronal cells that support neuron health such as glia?

To address these questions we use state-of-the-art in vivo microscopy, genome engineering, genetics and molecular and cell biology techniques.