Edinburgh Research Archive logo

Edinburgh Research Archive

University of Edinburgh homecrest
View Item 
  •   ERA Home
  • Royal (Dick) School of Veterinary Studies
  • Royal (Dick) School of Veterinary Studies thesis and dissertation collection
  • View Item
  •   ERA Home
  • Royal (Dick) School of Veterinary Studies
  • Royal (Dick) School of Veterinary Studies thesis and dissertation collection
  • View Item
  • Login
JavaScript is disabled for your browser. Some features of this site may not work without it.

Refining and applying comparative proteomics workflows to uncover novel regulators of neuronal stability between childhood and adult-onset degenerative diseases

View/Open
KlineRA_2022.pdf (24.40Mb)
Date
07/06/2022
Item status
Restricted Access
Embargo end date
07/06/2024
Author
Kline, Rachel Ann
Metadata
Show full item record
Abstract
Early structural, functional and molecular dysregulation in the synapse unites the majority of neurodegenerative conditions, including those without any current available therapeutic option. These similarities suggest that conserved pathways may promote a common neurodegenerative phenotypes, regardless of age of onset, aetiology (genetic or otherwise), or affected neuronal population. Identifying the molecular dysregulation linking synaptic vulnerability across multiple conditions may therefore uncover targetable regulatory elements conserved across the neurodegenerative spectrum irrespective of aetiological origin. Tandem mass tagging-based proteomic profiling of pre-symptomatic SMA (spinal muscular atrophy – a childhood MND), ALS type 8 (amyotrophic lateral sclerosis - a late adult onset MND), and CLN3 (a juvenile NCL) models through parameters of regional vulnerability and pathological gene “dose” identified 200 conserved candidates altered in a dose-dependent manner with respect to their distinct causative mutations. Predictive in silico analyses confirmed that these individual protein alterations interact hierarchically to mediate dysregulation in a broader cellular context, including changes in a number of metabolic pathways. In vivo genetic and pharmacological manipulation of the majority of conserved candidates, as well as the retinoid-X-receptor (RXR)—the strongest predicted upstream “master regulator” of identified conserved protein alterations—regulates degeneration across Drosophila models of both CLN3 and ALS type 8. Investigation within the synaptic proteomes of differentially vulnerable regions in post mortem brains reveals that these regulatory cascades are also activated in a regional-vulnerability-dependent manner in spontaneous ALS with predictive mechanistic regulation of lipid homeostasis. These results provide evidence for shared pathogenic mechanisms promoting a common degenerative signature that link otherwise unrelated degenerative diseases affecting every stage of the human lifecourse.
URI
https://hdl.handle.net/1842/39040

http://dx.doi.org/10.7488/era/2291
Collections
  • Royal (Dick) School of Veterinary Studies thesis and dissertation collection

Library & University Collections HomeUniversity of Edinburgh Information Services Home
Privacy & Cookies | Takedown Policy | Accessibility | Contact
Privacy & Cookies
Takedown Policy
Accessibility
Contact
feed RSS Feeds

RSS Feed not available for this page

 

 

All of ERACommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsPublication TypeSponsorSupervisorsThis CollectionBy Issue DateAuthorsTitlesSubjectsPublication TypeSponsorSupervisors
LoginRegister

Library & University Collections HomeUniversity of Edinburgh Information Services Home
Privacy & Cookies | Takedown Policy | Accessibility | Contact
Privacy & Cookies
Takedown Policy
Accessibility
Contact
feed RSS Feeds

RSS Feed not available for this page