Prediction of a Shared Enzymatic Machinery Between Parkinson's Disease Selectively Vulnerable Neurons

A specific set of brainstem nuclei have been indicated to be susceptible to degeneration by histopathological analysis of subjects with suggested prodromal or established early Parkinson's disease. We hypothesise that neuronal vulnerability reflects shared cellular and molecular phenotypic characteristics that confer selective susceptibility to degeneration. Neuronal cellular and molecular phenotypic specification is mainly the cumulative result of a set of transcription factors active during the development of the nervous system. By manual curation of developmental biology literature, we comprehensively reconstructed an anatomically resolved cellular developmental lineage of the mouse adult neurons that are homologous to neurons selectively vulnerable to degeneration in prodromal and early Parkinson's disease. The set of transcription factors required for developmental specification of each selectively vulnerable neuronal population was used to predict the corresponding set of downstream genes. In tandem with analysis of mouse brain transcriptomic data, we preditced the set of genes upregulated in each susceptible neuronal populations. Upregulated metabolic genes, in combination with manual reconstruction of neuronal metabolism, was used to generate constraint-based metabolic models for each susceptible neuronal population. Comparative analysis of the metabolic capabilities of neurons susceptible and resistant to degeneration was used to predict metabolic susceptibilites in Parkinson's Disease.