Volume 1, Issue 4
September 2001

What's Inside

Excessive iron accumulation has been reported in the brains of patients with Parkinson’s or Alzheimer’s disease, and it has been postulated that abnormal iron accumulation in the brain is neurotoxic through the generation of free radicals. However, it remains unclear whether iron-induced oxidative stress is a primary or a secondary event in the process that leads to neuronal death. Two recent reports suggest that - at least in some cases - iron toxicity may be a primary event in neurodegeneration.

Neuroferritinopathy Causative Gene Identified
In recent years, Curtis et al have described a previously unrecognized adult-onset neurodegenerative disease that affects the basal ganglia and is associated with iron accumulation. The disease is dominantly inherited and presents with extrapyramidal symptoms and low ferritin serum levels. Histopathology is characterized by lesions in the globus pallidus with abundant spherical inclusions containing aggregates of ferritin and iron. Additionally, axonal swellings are found throughout the brain and are immunoreactive for ubiqutin and tau. Within the brain, only the basal ganglia appear to be affected. Outside the brain, organs such as the pancreas, liver, and heart that are typically affected in iron accumulation disease, appear to function normally.

Using linkage analysis and positional cloning in an extended family from Northern England, Curtis et al, report that the causative mutation lies in the gene encoding a subunit of ferritin. More precisely the mutation affects the carboxy terminal of the L chain of ferritin and consists of the insertion of an adenine in the gene. The same mutation was found in five apparently unrelated subjects with similar extrapyramidal symptoms and low ferritin serum levels.

Ferritin, the major iron-storage protein, is composed of 24 subunits of two types, heavy (H) and light (L). These units form a hollow sphere in which iron precipitates are sequestered. Curtis et al. suggest that the mutation may alter ferritin’s function and stability, perhaps allowing inappropriate release of iron from the mutated protein. Ferritin is normally synthesized in the cell body where it sequesters iron. It is then transported down the axons to nerve terminals where it provides iron to the synapse. Based on the crystal structure of ferritin, the authors propose that the mutated ferritin may be less stable than normal ferritin and may release iron within the axon, causing iron-dependent oxidative damage of axons and loss of function of a number of axonal proteins. This axonally-initiated toxicity may explain why significant pathology is seen only in the central nervous system.

Interestingly, mice that lack iron-regulatory protein 2 and that overexpress both H and L ferritin chains show a similar pattern of neurotoxicity. In this case, axonal release of iron could be due to the degradation of overexpressed ferritin by lysosomes present in distal axons.

Hallervorden-Spatz Syndrome: Gene Defect Identified
Hallervorden-Spatz Syndrome (HSS) is a progressive, autosomal neurodegenerative disorder of childhood and adolescence. The disease usually presents with stiffness of gait and distal wasting. Muscle tone is both spastic and rigid. Reflexes are hyperactive, and the toes are usually upgoing. Dystonia is sometimes present. Pigmentary degeneration of the retina is seen in some families. In others optic atrophy is observed. The course of the illness typically spans a dozen years. Several clinical variants have been described, with relatively stereotyped courses within families, suggesting genetic heterogeneity. Diagnosis is confirmed by demonstration of increased uptake of the iron isotope ⁵⁹Fe by scanning the basal ganglia. Definite diagnosis requires autopsy. Olive or golden-brown discoloration of the globus pallidus is characteristic and is due to granules of an iron-containing lipopigment located inside and outside neurons. The affected tissues contain an increased amount of iron and axonal swellings.

Using linkage analysis of an extended Amish pedigree, Zhou et al had previously defined an interval on chromosome 20p13 that contained the gene for HSS. They now report that the culprit gene encodes a pantothenate kinase (PANK2), an essential regulatory enzyme in the biosynthesis of CoenzymeA (CoA). HSS is the first inborn error of pantothenate metabolism

CoA is the major acyl carrier and plays a central role in intermediary and fatty acid metabolism . There could be many reasons why a PANK2 defect causes neurotoxicity. First, CoA depletion results in defective membrane biosynthesis. This could explain the retinopathy frequently observed in HSS, since rod photoreceptors continually generate membranous discs.

Second, a PANK2 defect could alter iron concentrations in the brain indirectly by affecting cysteine concentrations. Phosphopantothenate, the product of PANK2, normally condenses with cysteine in the next step in the synthesis of CoA. Phosphopantothenate deficiency leads to increased concentrations of cysteine within neurons. Not surprisingly therefore, the concentrations of cysteine have been found to be abnormally high in the globus pallidus of HSS patients.

How could increased concentrations of cysteine cause neuronal damage? Probably through the formation of free radicals. Cysteine undergoes rapid auto-oxidation in the presence of iron resulting in free radical production. In addition, iron-induced lipid peroxidation, a likely mechanism of secondary pathogenesis in HSS, is enhanced by free cysteine.

The authors conclude that it may be possible to slow the progression of HSS by therapeutically delivering compounds that bypass PANK2 and drive CoA synthesis. This study also raises the possibility that errors in pantothenate metabolism may represent a common pathway in a number of other neurodegenerative diseases.

Curtis ARJ, Fey C, Morris CM, et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nature Genetics 2001; 28: 350-354.

Zhou B, Westaway SK, Levinson B. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nature Genetics 2001; 28: 345-349.

Reviewed by Rouault TA. Iron on the brain. Nature Genetics 2001; 28: 299-300.

The purpose of the American Society of Experimental NeuroTherapeutics is:

– To provide a forum for broadly defined interest areas of academia, government, and industry concerned with the field of neurotherapeutics.

– To promote dialogue, understanding and cooperation among the interested groups.

– To develop information and seek consensus on matters germane to the organization’s mission.

– To organize education and training for healthcare practitioners, biomedical scientists and officials participating in the neurotherapeutics field.

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