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A postsynaptic pathway of TDP-43-mediated pathology in ALS

Amyotrophic Lateral Sclerosis (ALS) is characterised by the vulnerability of the motor system. Circuit dysfunction within the motor cortex is likely to be an early disease event, occurring prior to clinical symptoms, however why the motor cortex is vulnerable and the mechanisms driving changes to this network are unknown. We have found that TDP-43, the protein that is most frequently found in cytoplasmic aggregates in ALS, is involved in maintaining neuronal synapses in mouse models of ALS - regulating the number and maturation of dendritic spines. Spine changes occur well before symptom onset in the motor cortex, but not the somatosensory cortex, indicating that this is one of the earliest pathological changes associated with TDP-43. We advanced these finding through the application of 2-photon live imaging to reveal that the motor cortex exhibits higher turnover rates of dendritic spines in comparison to other brain regions, that is compromised in the presence of mutant TDP-43. The action of misprocessed TDP-43 at the spine may be due to its role in activity-dependent RNA translation. We have identified that mutant TDP-43 drives increased expression of TDP-43 in the cytoplasm and causes alterations in the composition and localisation of AMPA receptor proteins specifically at the spine head. We have identified that the motor cortex may be specifically vulnerable to TDP-43-mediated dendritic spine deficits. Outcomes of this study identify mechanisms that may drive ALS, and also provide a greater understanding of the vulnerability of the motor cortex, informing therapeutic development and subsequent clinical trial design for all future therapeutic interventions.

Date Monday, 26 November 2018
Time 1:00pm - 2:00pm
Audience All University
Event Category Health Sciences
Event Type Departmental Seminar
LocationHercus d'Ath Lecture Theatre, Great King Street

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