Witnessing the mechanistic insights of neuronal apoptosis from a global transcriptomic view: comparative microarray analysis of multiple neurodegenerative models

Apoptosis is the earliest identified mode of cell death characterized by its closely coordinated signaling mechanisms that put the cell to its demise without disruption to its microenvironment. It is the most reported cause of neuronal death seen in the pathogenesis of numerous neurodegenerative disorders. The current focus of this review revolves around the significance of the major biological processes (e.g. oxidative stress, endoplasmic reticulum/lysosomal disruption, mitochondrial respiratory dysfunction and ubiquitin-proteasome system inhibition) at work in the induction of neuronal apoptosis during neurodegeneration in various central nervous system diseases. To further complement and substantiate the existing findings, comparative microarray analysis was conducted on five neurodegenerative global gene profiles from our laboratory to provide comprehensive temporal elucidation of the implication of these neuropathological mechanisms during neuronal apoptosis at the transcriptional level. These transcriptomic profiles were derived from the application of widely employed pharmacological agents on in vitro rodent models to mimic neuropathological hallmarks. They comprise of lactacystin (proteasomal inhibitor), Glu (excitotoxicity inducer), nitric oxide (source of reactive nitrergic and oxygen species), hypochlorous acid (source of reactive chlorinergic and oxygen species) and rotenone (mitochondrial complex I inhibitor) commonly used to model chronic neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Down syndrome as well as acute neurological disorders such as stroke and traumatic brain injury. Mediation of neuronal injury and apoptosis by any one agent is not mutually exclusive to any particular neurodegenerative condition, but at most times demonstrates simultaneous involvement across the neurodegenerative disease spectrum. This is an indirect indication of a significant commonality of signaling cascades in the pathogenesis of most neurodegenerative diseases, and that apoptosis plays a major role in the trigger of these downstream mechanisms. Subsequently, this provides the opportunity for identification of novel biological targets whose manipulation would provide beneficial broad-spectrum neurodegenerative disease therapeutic intervention.