Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.631959
Title: Prion-like mechanisms of TDP-43 in ALS
Author: Smethurst, P.
ISNI:       0000 0004 5358 3641
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Abstract:
Mounting evidence now suggests that many neurodegenerative diseases behave in a similar manner to prion diseases. Although there is no demonstrable infectivity of these conditions, numerous biological studies show that aggregated proteins linked to each of these diseases can behave in a prion-like manner at the cellular level. One of the conditions shown to have prominent clinical and cellular prion-like behaviour, in terms of focal onset and spread of pathology, is amyotrophic lateral sclerosis (ALS). Indeed, it is now well recognised that TDP-43 is the main component of the ubiquitinated inclusions observed in the neurons of the brain and spinal cord in patients with ALS and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). TDP-43 is deposited in more than 90% of sporadic ALS cases, and mutations in the TARDBP gene encoding for TDP-43 are found to cause ALS. In this thesis, we show that the levels of TDP-43 are significantly elevated in different regions of the CNS in ALS patients compared to controls. We also demonstrate that pathological TDP-43 has a degree of protease resistance, and can be seeded into cell culture directly from ALS CNS tissue to reproduce the characteristic TDP-43 pathology. In addition to this we demonstrate that pathologically aggregated and phosphorylated TDP-43 can propagate from cell to cell in a prion-like manner. We also investigated whether this TDP-43 pathology can be transmitted in vivo to wild type mice, and utilised a novel MRI imaging technology to attempt to non-invasively detect protein aggregation in the spinal cord of the well characterised SOD1 G93A ALS mouse model. In summary, we demonstrate that TDP-43 displays characteristic cellular prion-like behaviour, which could potentially explain some of the pathological mechanisms in ALS, and highlights potential mechanisms for therapeutic investigation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.631959  DOI: Not available
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