Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of the motor neurons in the cerebral cortex, brain stem, and spinal cord. However, the mechanisms that regulate the initiation and/or progression of motor neuron loss in this disease remain enigmatic. Cell-cycle proteins and transcriptional regulators such as cyclins, cyclin-associated kinases, the retinoblastoma gene product (pRb), and E2F-1 function during cellular proliferation, differentiation, and cell death pathways. Recent data has implicated increased expression and activation of various cell-cycle proteins in neuronal cell death. We have examined the expression and subcellular distribution of G(1) to S phase cell-cycle regulators in the spinal cord, motor cortex, and sensory cortex from clinically and neuropathologically diagnosed sporadic ALS cases and age-matched controls. Our results indicate hyperphosphorylation of the retinoblastoma protein in motor neurons during ALS, concurrent with increased levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor neurons and glia. These data suggest that G(1) to S phase activation occurs during ALS and may participate in molecular mechanisms regulating motor neuron death.