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The role of ALS associated genes and c-Jun in neurodegeneration

Acosta Saltos, AD; (2016) The role of ALS associated genes and c-Jun in neurodegeneration. Doctoral thesis , UCL (University College London). Green open access

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The molecular pathways mediating motor neuron degeneration in Amyotrophic lateral sclerosis and axonal regeneration following peripheral nerve injury remain elusive. The transcription factor c-Jun, an important orchestrator of axonal regeneration, has been found upregulated in the spinal cord of ALS cases and the SOD1G93A mouse model of the disease. However the functional role of c-Jun in ALS degeneration has not been defined. The current thesis demonstrates that genetic deletion of c-Jun from neurons and neuroglia prolonged the lifespan of SOD1G93A mice. Associated with this effect on survival, motor neuron loss, axonal loss and neuroinflammation were attenuated in c-Jun deficient SOD1G93A mice. Interestingly, in addition to the neurodegenerative changes, motor neuron pools affected by ALS disease in SOD1G93A mice demonstrated a disease-mediated axotomy response, which was characterised by the expression of regeneration associated proteins and was dependent on the expression of c-Jun. Since the expression of regeneration-associated proteins changes in ALS, it was next investigated whether the expression of ALS-associated proteins changes during axonal regeneration. This thesis demonstrates that the pattern of expression of ALS associated proteins; TDP-43, FUS and alsin, does indeed change within motor neurons following facial nerve axotomy, in wild type mice. In addition, it describes for the first time that alsin protein may localise to the cellular nucleus in uninjured motor neurons. Interestingly, axotomy resulted in a transient clearing of the normal nuclear immunoreactivity for all three studied proteins. The size of this effect was dependent on the severity of nerve injury for TDP-43 and alsin. Finally, to begin to investigate the functional role of ALS associated genes in axonal regeneration the A315T TDP-43 model of ALS was assessed following facial nerve transection. Genetic overexpression of ALS associated A315T mutant TDP-43 resulted in delayed motor function recovery following facial nerve axotomy in mice. This effect was associated with increased perineuronal inflammation and increased motor neuron expression of the adhesion molecule 4 CD44 but reduced perineuronal sprouting. However, overexpression of A315T mutant TDP-43 did not affect anatomical target reinnervation, motor neurons loss or the pattern of expression of other regeneration associate proteins. Thus, this thesis demonstrates that the molecular changes in ALS-associated motor neurodegeneration and peripheral nerve injury-associated regeneration overlap, and it suggests that insights obtained from studying one of these processes may be applied to further understand the other.

Type: Thesis (Doctoral)
Title: The role of ALS associated genes and c-Jun in neurodegeneration
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Third party copyright material has been removed from ethesis.
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 Population Health Sciences > UCL EGA Institute for Womens Health
URI: https://discovery.ucl.ac.uk/id/eprint/1473955
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