Iron is an essential element, and its ability to readily lose and accept electrons makes it a vital part of the enzymes that catalyse redox reactions. But this property also makes iron a hazard to cells as it catalyses the formation of free radicals, which damage cellular structures and DNA. To prevent this, some organisms have evolved ways to sequester and transport iron around the body. In humans, increased iron deposition in the brain's basal ganglia occurs with ageing and markedly in several neurodegenerative diseases, such as Huntington and Alzheimer. Two groups now report genetic defects in two human neurodegenerative disorders characterized by such deposition, strongly indicating that iron accumulation has a key role in the aetiology of neurodegeneration.

Bing Zhou and colleagues mapped Hallervorden–Spatz syndrome (HSS) — an early-onset, recessive, neurodegenerative disorder — to a region on chromosome 20 in an Amish pedigree. By screening for mutations in brain-expressed, candidate genes in this interval, they found a 7-bp deletion in a gene called PANK2 in this pedigree and in other HSS patients. The ubiquitously expressed PANK2 encodes pantothenate kinase, an enzyme in the coenzyme A (CoA) biosynthetic pathway. But how does altered CoA synthesis lead to specific neurological defects? PANK2 mutations most likely cause neurodegeneration secondarily to their effect of blocking the CoA pathway by causing secondary metabolites to accumulate. Indeed, such a metabolite, cysteine, accumulates in the basal ganglia of HSS patients to potentially lethal effect because cysteine not only is cytotoxic but also produces free radicals in the presence of iron. Such a combination could damage neuronal cells that are already stressed by impaired membrane biosynthesis caused by depleted CoA levels, so leading to cell death and neurodegeneration.

Unlike the secondary neurodegenerative effects of PANK2 mutations, in a novel, dominantly inherited, late-onset disorder studied by John Burn's group — neuroferritinopathy — neurodegeneration is probably caused by the altered storage of iron. This group identified a mutation in FTL , which encodes ferritin light chain — a subunit of ferritin, the molecule that stores and sequesters free iron — in an English pedigree. FTL was considered a candidate gene because of its map position and the suspected involvement of iron in neurodegeneration. The same mutation was found in five other neurodegenerative disease cases, who share a founder haplotype with the original pedigree. Because of the disorder's rarity, Curtis et al. believe that the FTL mutation acts as a dominant negative by encoding a structurally altered subunit that is incorporated into ferritin, disrupting its function, perhaps by preventing the normal transfer of iron into and out of this molecule. Studies in mice will no doubt follow these exciting findings, providing greater insight into how iron accumulation contributes to the cause and progression of neurodegenerative disease.