Refining and applying comparative proteomics workflows to uncover novel regulators of neuronal stability between childhood and adult-onset degenerative diseases
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Date
07/06/2022Item status
Restricted AccessEmbargo end date
07/06/2024Author
Kline, Rachel Ann
Metadata
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.