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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.