I am fascinated by the beautiful but complicated shape of individual neurons, and the complex intracellular logistics required to form, maintain and remodel these cells throughout life.
Neurons extend processes that cover vast territories, which allow them to directly connect with cells distant from the soma. Our research interest is to understand how neurons integrate the different extracellular cues that they receive at distinct parts of the cell in time and space to maintain and adapt their structure and connectivity. To this end, we study the interplay of short- and long-range trafficking and signalling, and how these events ultimately converge to initiate changes in neuronal morphology and physiology.
The formation and maintenance of neuronal connections requires morphological changes and is tightly coupled to activity-dependent events. In this regard, the neurotrophin BDNF provides an example of a highly regulated growth factor that triggers intracellular processes to initiate changes in cell shape. Moreover, its precursor, proBDNF, is also biologically active with largely opposing actions to those of mature BDNF, thus allowing for tightly controlled, bi-directional modulation of neuronal morphology by a single growth factor.
Our current research questions are:
What are the differential signals generated by pro- and mature neurotrophins?
We aim to broaden our understanding of the intracellular pathways activated by proneurotrophins by employing unbiased proteomic approaches, thus extending our work on mature BDNF and NT-3 signalling to include proBDNF. We are using the results of these screens as well as candidate approaches to dissect the molecular mechanisms of neurotrophin action on the cytoskeleton.
What decides if signals are processed locally or transmitted over long distances?
Morphological changes may be localised, to promote the growth or pruning of individual axonal and dendritic branches, or they can stimulate or suppress growth of the entire neuron. Using characterized nuclear responses to neurotrophin signalling as well as changes in morphology as read-outs, we are dissecting local processing of signalling cascades versus signal propagation along axons in compartmented devices.
In many neurodegenerative diseases, such as Alzheimer’s and Huntington’s disease, as well as motor neuron degeneration, impairment in axonal transport processes and dying back of neuronal connections precede cell death and are concurrent with onset of symptoms. In these and other instances of acute or progressive neuronal injury and degeneration, the balance between favourable and harmful signals is shifted. Understanding the signals and intracellular mechanisms that guide the remodelling of neuronal morphology in both supportive and adverse conditions may provide insights into these diseases and help direct therapeutic approaches.
Grace Hallinan. NeuroTraffic: Orientated neuronal networks for investigating mechanisms of tau propagation. Alzheimer’s Research UK/ VC scheme
Prutha Patel. Are neurons that express mutant forms of tau fully competent to process BDNF-TrkB signalling? Gerald Kerkut Trust/CfBS.
Affiliate research group(s)
Molecular and Cellular Biosciences,Southampton Neuroscience Group (SoNG),Institute for Life Sciencecs (IfLS)
This project aims to delineate the cellular mechanisms that regulate cargo identification during endocytosis and autophagy and their impact on cell signalling and morphogenesis.
Dr Katrin Deinhardt
University of Southampton SO17 1BJ
Telephone:(023) 8059 4353