The molecular mechanisms that regulate neuronal cell death in neurodegenerative diseases remain unclear. During neurologic diseases numerous neuronal and glial intracellular signaling pathways are activated by changes within the extracellular environment, which culminate in alterations of nuclear proteins and gene expression. Among the proteins activated or expressed during neurodegenerative diseases include proteins that function during the cell cycle. Early events in cell cycle activation include transition from the G1 to S phase of the cell cycle, which is regulated by the activity of proteins from the retinoblastoma (pRb) and E2F gene families of transcriptional regulators. Hyperphosphorylation of pRb induces the activation of E2F proteins at the G1-to-S cell cycle transition. Using brain and spinal cord tissues from non-demented control, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) patients, we identified increased levels of hyperphosphorylated pRb in AD and ALS patients. In addition, we observed altered subcellular distribution of E2F-1 during AD and ALS. Our results suggest that activation and re-distribution of early cell cycle transcriptional regulators occurs in both AD and ALS.