A Golgi fragmentation pathway in neurodegeneration.

The Golgi apparatus processes intracellular proteins, but undergoes disassembly and fragmentation during apoptosis in several neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer's disease. It is well known that other cytoplasmic organelles play important roles in cell death pathways. Thus, we hypothesized that Golgi fragmentation might participate in transduction of cell death signals. Here, we found that Golgi fragmentation and dispersal precede neuronal cell death triggered by excitotoxins, oxidative/nitrosative insults, or ER stress. Pharmacological intervention or overexpression of the C-terminal fragment of Grasp65, a Golgi-associated protein, inhibits fragmentation and decreases or delays neuronal cell death. Inhibition of mitochondrial or ER cell death pathways also decreases Golgi fragmentation, indicating crosstalk between organelles and suggesting that the Golgi may be a common downstream-effector of cell death. Taken together, these findings implicate the Golgi as a sensor of stress signals in cell death pathways.