BACKGROUND:
Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) are major neurodegenerative disorders that collectively affect millions worldwide. Despite distinct clinical features, these conditions share overlapping genetic risk factors, including apolipoprotein-E (ApoE) and alpha-synuclein (aSyn). ApoE has protective (E2, Christchurch) and risk-related (E3, E4) isoforms, while aSyn mutations (A53T, E46K) promote early aggregation and neurotoxicity. How the protein interaction networks of ApoE and aSyn converge on healthy vs disease mechanisms remains unclear.
METHODS:
We are applying TurboID proximity labeling proteomics to define the in vivo isoform interactomes of ApoE and aSyn. Using AAV delivery, TurboID-tagged ApoE (E2, E3, E4, Christchurch) is expressed in astrocytes, and aSyn (WT, A53T, E46K) in neurons, to identify cell and isoform-specific protein networks. Western blot and immunofluorescence microscopy are used to confirm TurboID probe expression and candidate-interactor biotin labeling. Biotin-labeled candidate interaction partners are enriched using streptavidin magnetic beads and purified for precision LFQ mass spectrometry.
RESULTS:
Preliminary data in pilot animals indicate that wild-type aSyn and ApoE3 may share many interacting proteins enriched in axonal components, neurofilament structures, and neurodegeneration-related pathways. This unexpected overlap suggests that ApoE and aSyn may influence common axonal integrity networks essential for neuronal health. We hypothesize that protective variants (ApoE2/Christchurch, WT aSyn) preserve these axonal networks, while risk variants (ApoE4, mutant aSyn) destabilize them, contributing to early axonal dysfunction.
CONCLUSION:
Axonal dysfunction represents a potentially reversible, early event in neurodegeneration, distinct from the irreversible aggregation observed in late disease stages. By mapping how ApoE and aSyn variants differentially regulate axonal protein-protein interaction networks, this work aims to establish a unifying molecular framework linking genetic risk to shared cellular pathology across AD, PD, and DLB.