Pathophysiological disease mechanisms underlying motor neuron dysfunction in MND

About the project

Research in the Miles lab aims to reveal novel pathophysiological mechanisms that underlie motor neuron dysfunction and eventual degeneration in MND. We are currently utilising a combination of electrophysiological and anatomical analyses applied to animal and human stem cell-based models to investigate deleterious interactions between glial cells and motor neurons, perturbations in synaptic connectivity, and changes in ion channel function that effect motor neuron excitability.

We hope to reveal novel therapeutic targets for the development of much-needed treatment strategies aiming to improve motor neuron function and survival in MND.

Funder(s)

MND Association, MND Scotland

Publication(s)

Broadhead MJ, Doucet K, Kantelberg OG, Zhu F, Grant SGN, Horrocks MH, Miles GB

Synaptic expression of TAR-DNA-binding protein 43 in the mouse spinal cord determined using super-resolution microscopy

Frontiers in Molecular Neuroscience. 2023. 16:1027898

DOI: 10.3389/fnmol.2023.1027898

McIntosh J, Mekrouda I, Dashti M, Giuraniuc C, Banks RW, Miles GB, Bewick GS

Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS: dysfunction then disruption of postsynaptic structure precede motor symptoms.

Frontiers in Molecular Neuroscience. 2023. 16:1169075.

DOI: 10.3389/fnmol.2023.1169075

Broadhead MJ, Bonthron C, Waddington J, Smith W V, Lopez MF, Burley S, Valli J, Zhu F, Komiyama NH, Smith C, Grant SGN, Miles GB

Selective vulnerability of tripartite synapses in amyotrophic lateral sclerosis.

Acta Neuropathologica. 2022. 143:471–486

DOI: 10.1007/s00401-022-02412-9

Zhao C, Devlin AC, Chouhan AK, Selvaraj BT, Stavrou M, Burr K, Brivio V, He X, Mehta AR, Story D, Shaw CE, Dando O, Hardingham GE, Miles GB, Chandran S

Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology.

Glia. 2020. 68(5):1046-1064

DOI: 10.1002/glia.23761

Devlin AC, Burr K, Borooah S, Foster JD, Cleary EM, Geti I, Vallier L, Shaw CE, Chandran S, Miles GB

Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Nat Commun. 2015 Jan 12;6:5999

DOI: 10.1038/ncomms6999