Dr Alison Twelvetrees
My research is focused on understanding how the microtubule transport system contributes to neuronal health and disease. Neurons form complex extended cellular structures, which are essential for their function. This also presents a huge challenge that is unique to neurons; the need for a constant stream of organelles, proteins, RNA and signals, transported over very large distances, reaching the right destination at the right time. My research is focused on understanding how microtubule transport involving the motor proteins dynein and kinesin contributes to neuronal health and disease. I apply cutting edge cell biological, biochemical and biophysical approaches to visualize these processes in neurons over a broad range of spatial-temporal scales; from sub-second motility of single molecules to cellular behaviours over many hours. By conducting this research within SITraN we aim to maximise the translation of our work for drug discovery.
Neurons form complex extended cellular structures. For example, motor neurons have cell bodies in the spinal cord whilst extending axons down to the muscles of the hands and feet; the axons of motor neuron can therefore be over a metre long. This extended morphology is essential for neuronal function, but also presents huge challenges that are unique to neurons.
The majority of newly synthesized protein is made in the neuronal cell body and then actively transported down the axon to its site of use, up to one meter away. In addition, retrograde transport (from the synapse to the cell body) is required to maintain the health of the axon by removing aging proteins and organelles from the distal axon and relaying neurotrophic signals back to the cell body. All long distance transport events in the axon fall under the label of ‘axonal transport’. However, this label masks a complex set of co-dependent intracellular trafficking events of a huge array of cargos critical for neuronal health. Despite this complexity, all axonal transport events are carried out by the same set of machinery: microtubules and microtubule motor proteins (dynein and kinesins).
There is now a large body of evidence demonstrating deficits in axonal transport in multiple unrelated adult-onset neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, as well as motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegias (HSPs). In addition, deficits are frequently found as an early event in disease models.
Our research is focused on understanding how the microtubule transport system contributes to neuronal health and disease. The primary aim is to define neuron-specific functions of microtubule motors, established through neuron specific protein subunits or cellular environments, and ask how these are altered in disease models. We do this by applying the tools of biochemistry and biophysics within neuronal cells. By conducting this research within SITraN we aim to maximise the translation of our work for drug discovery. As all axonal transport is driven by dynein and kinesins, therapeutic strategies aimed at this system could have broad applicability to many diseases. However, there are many fundamental unknowns in our understanding of how motor proteins function as part of regulated systems within neurons, and this is a roadblock in developing treatments. Current projects are focused around the following themes:
Understanding how neuron specific subunits of motor proteins tailor motor protein function to carry out neuron specific cellular tasks.
Dissecting kinesin activation mechanisms to understand the molecular level difference between slow and fast axonal transport.
Directly addressing if there is therapeutic potential in augmenting kinesin activity in neurons.
Developing new experimental strategies to study axonal transport in real time, both for basic science applications and drug screening strategies.
Further details can be found on the lab website: twelvetreeslab.co.uk
Sleigh JN, Vagnoni A, Twelvetrees AE, Schiavo G (2017). Methodological advances in imaging intravital axonal transport. F1000Research. 6(F1000 Faculty Rev):200.
Twelvetrees AE, Pernigo S, Sanger A, Guedes-Dias P, Schiavo G, Steiner RA, Dodding MP, Holzbaur ELF (2016). The Dynamic Localization of Cytoplasmic Dynein in Neurons Is Driven by Kinesin-1. Neuron, 90(5):1000-15
Maday S, Twelvetrees AE, Moughamian AJ, Holzbaur ELF (2014). Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron, 84(2):292-309.
Zhang J, Twelvetrees AE, Lazarus JE, Blasier KR, Yao X, Inamdar NA, Holzbaur ELF, Pfister K, Xiang X (2013). Establishing a novel transgenic mouse line for studying neuronal cytoplasmic dynein under normal and pathogenic conditions. Cytoskeleton, 70:215–227
Twelvetrees AE, Hendricks AG, Holzbaur EL (2012). Snapshot: axonal transport. Cell, 149(4):950-950.e1
Hendricks AG, Twelvetrees AE, Holzbaur EL (2012). Intracellular Transport: New Tools Provide Insights into Multi-Motor Transport. Current Biology, 22(24):R1053-R1055
Twelvetrees AE, Yuen EY, Arancibia-Carcamo IL, Rostaing P, Lumb MJ, MacAskill AF, Humbert S, Triller A, Saudou F, Yan Z, Kittler JT (2010). Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron, 65(1):53-65
MacAskill AF, Rinholm JE*, Twelvetrees AE*, Arancibia-Carcamo IL, Muir J, Fransson A, Aspenstrom P, Attwell D, Kittler JT (2009). Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. *These authors contributed equally to this work. Neuron, 61(4):541-55
2017 - present, Vice Chancellor’s Fellow, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
2011 - 2017, Sir Henry Wellcome Postdoctoral Fellow, University of Pennsylvania, Cancer Research UK London Research Institute & UCL Institute of Neurology
2010 - 2011, Postdoctoral Research Scientist, Dept of Neuroscience, Physiology & Pharmacology, University College London
2005 - 2010, PhD in Molecular Neurobiology, Dept of Neuroscience, Physiology & Pharmacology, University College London
2001 - 2005, MSci Hons (1st Class) in Biochemistry, Imperial College London