Organelle interactions and dynamics in neurons
General Audience Summary
Understanding how neurons within the brain work together to produce movement, sensation, and cognition is one of the central challenges in scientific research. While much attention has been focused on how neurons communicate with one another, there is an equally important and lesser understood network of communication that happens within each individual neuron. This communication occurs between subcellular compartments (organelles) and plays a crucial role in enabling neurons to function and ultimately share information.
We, and others, have shown that disruption of these organellar communication pathways can lead to numerous neurological disorders, most notably neurodegenerative diseases such as Alzheimer’s, Parkinson’s and motor neuron disease.
Our lab is focussed on identifying the cellular machinery and mechanisms responsible for orchestrating communication between organelles. Our goal is to unravel how these factors enable neurons to function properly and understand what goes awry during neurodegenerative disease.
Strategic CIMR themes: Organelle Biology, Neurological Diseases. Membrane trafficking, Rare genetic diseases
Funding: Wellcome Trust
Research
Neuronal activity is the biological substrate of all cognitive function and is notably compromised in a wide variety of neurological disorders. The successful transmission of neuronal signals requires the rapid subcellular redistribution of ions, proteins and lipids in order to sustain action potential firing, recycle synaptic vesicles and organise synaptic membranes. Our lab studies how different organelles dynamically cooperate to enable this redistribution and thus facilitate neuronal transmission.
We are particularly interested in understanding sites of direct physical interaction between organelles, termed contact sites. Alongside classical vesicular transport mechanisms, contact sites act as central hubs for mediating the biosynthesis and redistribution of macromolecules across cells. Additionally, mutations in over 30 genes associated with contact sites have been identified as causative for a spectrum of neurodegenerative disorders including Alzheimer’s, Parkinson’s and motor neuron disease. Yet despite their importance, the molecular mechanisms by which contact sites operate remain poorly understood.
Our work exploits a combination of advanced microscopy, biophysics and multi-omics approaches to characterise the machinery and pathways involved in the formation, regulation, and function of contact sites in both healthy and diseased neurons. We aim to understand how contact site biology primes neurons for efficient neuronal transmission, and how these processes are corrupted in neurodegenerative disease.
Image: Multispectral image of a fibroblast cell expressing fluorescent markers to label the Golgi (red), mitochondria (green), lysosomes (cyan), peroxisomes (orange), stress granules (magenta).
Publications
Obara CJ*, Nixon-Abell J*, Riccio F, Moore AS, Hoffman DP, Shtengel G, Xu S, Schaefer K, Pasolli AH, Betzig E, Hess HF, Masson JB, Calderon CP, Blackstone C, Lippincott-Schwartz J. Motion of VAPB molecules reveals ER–mitochondria contact site subdomains (Nature) 2024
Nixon-Abell J, Ruggeri SF, Qamar S, Herling TW...St George-Hyslop P. ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes (BioRxiv) 2023
Laine RF*, Heil HS*, Coelho S, Nixon-Abell J, Jimenez A, Galgani T, Stubb A, Follain G, Culley S, Jacquemet G, Hajj B, Leterrier C, Henriques R. High-fidelity 3D live-cell nanoscopy through data-driven enhanced super-resolution radial fluctuation (Nature Methods) 2023
Zheng P, Obara CJ, Szczesna E, Nixon-Abell J, Mahalingan KK, Roll-Mecak A, Lippincott-Schwartz J, Blackstone C. ER proteins decipher the tubulin code to regulate organelle distribution (Nature) 2021
Liao Y, Fernandopulle M, Wang G, Hao L, Drerup K, Qamar S, Nixon-Abell J, Shen Y, Meadows W, Vendruscolo M, Knowles T, Nelson M, Patel R, Stephens C, Balaji V, Forrest L, St George-Hyslop P, Lippincott-Schwartz J, Ward M. RNA granules hitchhike on lysosomes for long-distance transport, utilizing Annexin A11 to tether RNA granules to lysosomes (Cell) 2019
Nixon-Abell J*, Obara CJ*, Weigel AV*, Li D, Legant WR, Harvey K, Betzig E, Blackstone C, Lippincott-Schwartz J. Increased spatiotemporal resolution reveals highly dynamic tubular matrices in the peripheral endoplasmic reticulum (Science) 2016
Nixon-Abell J*, Berwick DC*, Granno S, Spain VA, Blackstone C, Harvey K. Protective LRRK2 R1398H variant enhances GTPase and Wnt signaling activity (Frontiers in Molecular Neuroscience) 2016
