"We plan to test whether pharmacological targets and tool compounds identified by our drug discovery programme focused on restoring axonal transport have beneficial effects in vitro and in vivo in Alzheimer's disease models, modifying disease progression and disease endpoints." Giampietro Schiavo
UK DRI Group Leader
Working in multidisciplinary teams throughout his career, Prof Gipi Schiavo has a strong record of interdisciplinary research and translation of basic discoveries into medical outcomes. His laboratory played a major role in defining the mechanism responsible for the uptake of neurotrophins, their receptors and several virulence factors, such as tetanus toxin, and its coupling with the axonal retrograde transport pathway. In this UK DRI programme, he will apply his expertise and extensive knowledge of axonal transport to uncover therapeutics for neurodegenerative disorders.
1. At a glance
Restoring axonal transport deficits as a therapeutic strategy for neurodegenerative diseases
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. When these vital cells stop working and start to die, a person loses their ability to initiate and control muscle movement. With voluntary muscle action progressively affected, people may lose the ability to speak, eat, move and breathe. Sadly, there is currently no cure.
Axons are long, slender structures projecting from neurons and conduct electrical impulses, which serve to transmit information to different neurons, muscles and glands. Some neurons have very long axons – around 10,000 times as long as its cell body - so specialised transport processes are essential to supply axons with the molecules and nutrients they need to survive and stay healthy. But there is growing evidence that these systems may break down very early on in the development of ALS, and that this may also apply to several other neurodegenerative conditions, including Alzheimer's disease.
Prof Giampietro Schiavo is aiming to build our knowledge of the machinery responsible for maintaining axonal transport - deciphering what goes wrong in ALS, Alzheimer’s disease and other neurodegenerative diseases. His long-term goal is to discover potential new drugs that can restore the healthy functioning of neurons – helping to prevent, delay or reverse the onset of these devastating conditions.
2. Scientific goals
The team is investigating amyotrophic lateral sclerosis (ALS) as a disease paradigm to identify new common targets for pharmacological intervention in neurodegenerative diseases. Although several different mechanisms have previously been linked to the pathogenesis of ALS, a major shortcoming is the inability to distinguish between those that determine pathogenesis, and the cellular and molecular processes that are instead a consequence of the pathology, a consideration that extends to Alzheimer’s disease (AD) and other neurodegenerative conditions.
Growing evidence suggests that alterations in axonal transport processes supplying neurons with essential survival factors and/or fulfilling the energy requirements in the axon, occur very early in ALS pathogenesis and that this pathogenic mechanism may apply to several neurodegenerative conditions. The team has detected deficits in the axonal transport of signalling endosomes and mitochondria in motor neurons of an ALS mouse model expressing a human mutant form of superoxide dismutase 1 (SOD1G93A), both in vitro and in vivo, at different stages of ALS progression. Importantly, they found significant transport deficits even in pre-symptomatic mice. These alterations in transport are specific, since axonal transport was not affected in either sensory neurons or in motor neurons expressing wild-type SOD1, and extend to other mouse models of ALS, AD and other neurodegenerative conditions.
It is unlikely that these axonal transport deficits represent a non-specific sign of neuronal dysfunction, since axonal transport is not altered in motor neurons of a mouse model of spinal and bulbar muscular atrophy, another form of motor neuron disease, and expressing a human FUS mutant, even at a late symptomatic stage of the disease. In addition, axonal transport deficits caused by mutations in the dynein/dynactin motor complex and its adapters induce neurodegeneration and CNS deficits in mice and humans. Counteracting axonal transport deficits may thus represent a novel therapeutic strategy towards treating neurodegenerative diseases.
Main objectives and research goals:
1. Elucidating the machinery responsible for the regulation of axonal transport. Studying the composition, trafficking and signalling potential of axonal signalling endosomes and other cargo organelles.
2. Assessing the deficits in this process found in ALS, AD and peripheral neuropathies, both in vitro and in vivo.
3. Identification of innovative strategies aiming to restore physiological axonal transport levels in these pathologies. Discovering new therapeutic nodes and testing compounds in preclinical studies.
3. Team members
Dr James Sleigh (Senior Fellow)
Dr Sunaina Surana (Research Fellow)
Dr Nicol Birsa (Postdoctoral Researcher)
Dr Ioana Butnaru (Postdoctoral Researcher)
Dr Oscar Lazo (Postdoctoral Researcher)
Dr Jobert Vargas (Postdoctoral Researcher)
Reem Abouward (PhD Student)
Chiara Panzi (PhD Student)
Skye Stuart (PhD Student)
Within UK DRI:
- Dr Marc Aurel Busche, UK DRI at UCL
- Prof Paul Whiting, UK DRI at UCL
- Prof Dario Alessi, UK DRI Associate Member, MRC PPU, University of Dundee
Beyond UK DRI:
- Dr Alessio Vagnoni, King's College London
- Prof Mike Fainzilber, Weizmann Institute of Science
- Eli Lilly - studying the mechanism of tau release from rodent and human AD synapses and testing pharmacological tool compounds targeting specific pre-synaptic receptors.
Axonal transport, vesicular traffic, molecular motors, amyotrophic lateral sclerosis, motor neuron disease, peripheral neuropathies, Rab GTPases, tau biology and pathology
Optogenetics, CRISPR/CAS9-based screens, hiPSC-derived neurons, mouse models, high resolution live imaging
7. Key publications
Mech AM, Brown A-L, Schiavo G and Sleigh JN (2020) Post-synaptic morphology of mouse neuromuscular junctions is linked to muscle fibre type. bioRxiv.
Stuardo N, Moya-Alvarado G, Ramírez C, Schiavo G and Bronfman FC (2020) Optimized in vitro mono-biotinylated BDNF production after semiquantitative purification from HEK293 cells supernatant for axonal trafficking studies. J Vis Exp, in press.
Humphrey J, Birsa N, Milioto C, McLaughlin M, Ule AM, Robaldo D, Eberle A, Kräuchi R, Bentham M, Brown A-L, Jarvis S, Bodo C, Garone MG, Devoy A, Rosa A, Bozzoni I, Fisher EMC, Mühlemann O,Ruepp M-C, Mühlemann O, Schiavo G, Isaacs A, Plagnol V and Fratta P (2019) FUS ALS-causative mutations impair FUS autoregulation and splicing factor networks through intron retention. Nucl AcidS Res, in press. bioRxiv. doi: https://doi.org/10.1101/567735
Sleigh JN, Tosolini AP and Schiavo G (2020) In vivo imaging of anterograde and retrograde axonal transport in rodent peripheral nerves. Methods Mol Biol, in press.
Terenzio M, Di Pizio A, Rishal I, Marvaldi L, Di Matteo P, Kawaguchi R, Coppola G, Schiavo G, Fisher EMC and Fainzilber M (2020) Dynlrb1 is essential for dynein mediated transport and neuronal survival. Neurobiol Dis 140, 104816.
Rossor AM, Sleigh JN, Groves M, Muntoni F, Reilly MM, Hoogenraad CC and Schiavo G (2020) Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy. Acta Neuropathol Commun 8, 34.
Sleigh JN, Tosolini AP, Gordon D, Devoy A, Fratta P, Fisher EMC, Talbot K and Schiavo G (2020) ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo. Cell Rep 30, 3655-62. bioRxiv. doi: https://doi.org/10.1101/438812
Budzinska MI, Villarroel-Campos D, Golding M, Snijders AP, Weston A, Collinson L and Schiavo G (2020) PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors. J Cell Sci 133, jcs242412. PMID:32088381
Fellows AD, Rhymes ER, Gibbs KL, Greensmith L and Schiavo G (2020) The insulin-like growth factor 1 receptor regulates retrograde axonal transport of signalling endosomes in motor neurons. EMBO Rep 21, e49129.
Sebastián-Serrano A, Simón-García A, Belmonte A, Pose-Utrilla J, del Puerto A, García-Guerra L, Santos-Galindo M, Hernández IH, Schiavo G, Campanero MR, Lucas JJ and Iglesias T (2020) Differential regulation of Kidins220 isoforms in Huntington's disease. Brain Pathol 30, 120-13.
Kalinski AL, Kar AN, Craver J, Tosolini AP, Sleigh JN, Lee SJ, Hawthorne A, Brito-Vargas P, Miller-Randolph S, Passino R, Shi L, Wong VSC, Picci C, Smith DS, Bassell GJ, Willis DE, Havton LA, Sciavo G, Giger RJ, Langley B and Twiss JL (2019) Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition. J Cell Biol 218, 1871-90.
Vargas JNS, Wang C, Bunker E, Hao L, Maric D, Schiavo G, Randow F and Youle RJ (2019) Spatiotemporal control of ULK1 activation 1 by NDP52 and TBK1 during selective autophagy. Mol Cell 74, 1-16.
Shorrock HK, van der Hoorn D, Boyd PJ, Hurtado ML, Lamont DJ, Wirth B, Sleigh JN, Schiavo G, Wishart TM, Groen EJN and Gillingwater TH. UBA1/GARS dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy. Brain 2018; 141: 2878-94.
Gibbs KL, Kalmar B, Rhymes ER, Fellows AD, Ahmed M, Whiting P, Davies C, Greensmith L and Schiavo G. Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS. Cell Death Dis 2018; 9: 596.
Tyzack GE, Hall C, Sibley C, Cymes T, Forostyak S, Meyer IFG, Schiavo G, Zhang S-C, Gibbons G, Newcombe J, Patani R and Lakatos A. EphB1 induces a STAT3 activated astrocyte state that is perturbed in a human stem cell model of ALS. Nat Commun 2017; 8: 1164.
Sleigh JN, Gomez-Martin A, Wei N, Yang XL and Schiavo G. Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular homeostasis. Sci Rep 2017; 7: 9216.
Terenzio M, Schiavo G and Fainzilber M. Compartmentalized Signaling in Neurons: from Cell Biology to Neuroscience. Neuron 2017; 96: 667-679.