Neurodegeneration studies forge ahead

Access through your institution Buy or subscribe 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. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

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to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read

our FAQs * Contact customer support REFERENCES * ORIGINAL RESEARCH PAPER Zhou, B. et al. A novel pantothenate kinase gene (_PANK2_) is defective in Hallervorden–Spatz syndrome. _Nature

Genet._ 28, 345–349 (2001) Article  CAS  Google Scholar  * Curtis, A. R. J. et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease.

_Nature Genet._ 28, 350–354 (2001) Article  CAS  Google Scholar  * FURTHER READING Andrews, N. C. Iron homeostasis: insights from genetics and animal models. _Nature Rev. Genet._ 1, 208–217

(2000) Article  CAS  Google Scholar  Download references Authors * Jane Alfred View author publications You can also search for this author inPubMed Google Scholar RELATED LINKS RELATED

LINKS WEB SITE HSS Association RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Alfred, J. Neurodegeneration studies forge ahead. _Nat Rev Genet_ 2, 652

(2001). https://doi.org/10.1038/35088534 Download citation * Issue Date: 01 September 2001 * DOI: https://doi.org/10.1038/35088534 SHARE THIS ARTICLE Anyone you share the following link with

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