Smethurst, P;
(2014)
Prion-like mechanisms of TDP-43 in ALS.
Doctoral thesis , University College London.
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.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Prion-like mechanisms of TDP-43 in ALS |
| Event: | University College London |
| Keywords: | ALS,, Prion-like, TDP-43, Seeding, Propagation, Transmission, Neurodegeneration, Motor Neuron Disease |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1547228 |
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