The roles of iron and HFE genotype in neurological diseases

Iron accumulation is a recurring pathological phenomenon in many neurological diseases including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and others. Iron is essential for normal development and functions of the brain; however, excess redox-active iron can also lead to oxidative damage and cell death. Especially for terminally differentiated cells like neurons, regulation of reactive oxygen species is critical for cell viability. As a result, cellular iron level is tightly regulated. Although iron accumulation related to neurological diseases has been well documented, the pathoetiological contributions of the homeostatic iron regulator (HFE), which controls cellular iron uptake, is less understood. Furthermore, a common HFE variant, H63D HFE, has been identified as a modifier of multiple neurological diseases. This review will discuss the roles of iron and HFE in the brain as well as their impact on various disease processes. •Iron plays critical roles in development and aging of the brain.•Brain iron accumulation is present in multiple neurological diseases.•Homeostatic iron regulator, HFE, modifies clinical manifestations and underlying mechanisms of neurological diseases.•Iron targeting therapies are currently in development for PD, AD, NBIA, and ALS.