Title: Endoplasmic Reticulum Dynamics
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019. The Endoplasmic Reticulum (ER) is a multifunctional organelle, shaped as a contiguous network of membranous pipes extending throughout the cell periphery. Its morphology is imposed by membrane shaping proteins and benefits intercellular communication, allowing controlled distribution of ER luminal solutes (e.g. Ca2+ in muscular/neuronal signaling) and membrane bound components to distant sites and adjoining organelles. Mounting data from the last decade point to a critical role of ER morphology regulation in neuronal functioning, profoundly exemplified by yet to be rationalised association of ER morphogens with genetic neurodegenerations such as Hereditary Spastic Paraplegia, Retinitis Pigmentosa and their involvement in dementia related disorders such as Alzheimer’s. Based on in-house developed live cells super-resolution and single molecule tracking approaches we recently revealed the phenomenon of active ER luminal transport (a process dependent on ER morphology and its regulation). These new insights into fundamental ER structure–function relationship lead to the formulation of postulates that rationalise the particular vulnerability of neurons to faults in the regulation of ER morphology: Since the active ER transport is critical for timely longer distance communications (in supramicron range), its malfunction manifests specifically in cells with expensive ER-containing projections. Thus, neuronal geometry renders these cells particularly vulnerable for even slight perturbations in the efficiency of ER transport and morphology regulation. Processes that predictably require ER mediated communication across the nervous system cell encompass neuronal plasticity/pruning, dendrite formation, membrane health maintenance and secretory activities. Driven by these hypotheses as well as through unbiased approaches, the program seeks understanding of ER’s role(s) in neuronal (patho)physiology through integrating cell biology and state of the art imaging/probing tech, with clinical neurology in mind. Addressing the question of how the ER morphology and ER luminal transport play out in neuronal (dis)function is expected to lead to identification of neuroprotective targets. Objectives: 1) Identification of the ER luminal transport-generating machinery. This will facilitate 2) the development of tools to manipulate the ER luminal flow, which in turn will allow 3) the study of functionalities and features of neuronal cells that rely on active ER luminal transport; and 4) characterisation of the relationships between ER morpho-dynamics and specific neuronal functions. These will lead to understanding the role of the ER and its reliant neuronal cell functionalities vital for neuronal heath and facilitate identification of early intervention opportunities to prevent neuronal malfunction and/or degeneration associated with dementia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL