Neurodegenerative disorders are the second leading cause of death globally with 9 million deaths per year. The neuronal death in major parts of the brain is a clinical feature of these diseases. The reason behind this neural cell loss is still not clear. In Huntington’s Disease(HD), striatal medium spiny projection neurons are more vulnerable to cell death. In Amyotrophic Lateral Sclerosis(ALS), upper and lower motor neurons are lost in the initial stages of the disease and diminish as the disease progresses. Transcriptomic analysis with prediction of therapeutic targets and pathways may increase understanding of neuronal loss. Our study explores transcriptomic data obtained from Brodmann Area 9, Brodmann Area 4 for HD, and the spinal cord along with the frontal cortex for ALS. In this study, we analyzed the differential expression of genes and transcripts and illustrated the association of genes with variants. Further, we predicted the effect of variants on transcription factor binding, miRNA binding, and their target expression. Additionally, function interaction networks and co-expression networks are constructed to elucidate the role of genes and variants in disease-associated pathways/functions. The metabolic activity of the differentially expressed genes and the genome-scale metabolic model of variant-associated genes gave us insights into the metabolic role of potential therapeutic agents. We propose that abnormal neuroinflammation acts as a two-edged sword that indirectly affects the vasculature and associated energy metabolism. Genes expressed in immune cells are crucial for reducing neuronal cell loss. This integrative omics analysis provides insights to understand the molecular intricacies that govern disease progression which potentially pave the way for targeted therapeutic interventions.