Iron and ER stress in neurodegenerative disease

Neurodegenerative disease is a condition in which subpopulations of neuronal cells of the brain and spinal cord are selectively lost. A common event in many neurodegenerative diseases is the increased level of endoplasmic reticulum (ER) stress caused by accumulation and deposits of inclusion bodies that contain abnormal aggregated proteins. However, the basis of how ER stress contributes to the selective neuronal vulnerability and degeneration remain elusive. Iron accumulation in the central nerve system is consistently present in many neurodegenerative diseases. In the past 5 years we have begun to show a relationship between polymorphisms in the HFE (high iron) gene and the risk of neurodegenerative disorders. Recent findings have suggested a connection between ER stress and iron metabolism and neurodegeneration. Here we review how the different levels of chronic ER stress contribute to the different fates of neurons, namely the adaptive response and neuronal death. And, we discuss the roles of iron and HFE genotype in selective neuronal vulnerability and degeneration through modifying the ER stress level.