1 Laboratory of Molecular Genetics, Helsinki University Central Hospital, 00290 Helsinki, Finland
2 Deputy Editor, Physiological Genomics
NEURONAL CEROID LIPOFUSCINOSIS (NCL) is a neurodegenerative disease with five different clinical subtypes (four of childhood or juvenile onset, and one adult) mapped to the loci CLN1 through CLN8. Mutations have been identified in six distinct genes, two of them encoding soluble enzymes (PPT1, a protein thiolesterase, and TPP1, a serine protease) and four (CLN3, CLN5, CLN6, and CLN8) encoding novel transmembrane proteins (9). Physiologically, it is characterized by intracellular inclusion bodies within neurons, failures of lysosomal lipid handling, and accumulation of autofluorescent lipopigments (similar to lipofuscin) and ceroid in lysosomes.
Identification of these genes has facilitated the development of knockout mouse models (4, 6) that enable therapeutic trials for these severe brain disorders. One variant of the disase, Northern epilepsy (CLN8), has a spontaneously occurring mouse model: the mnd (motor neuron degeneration) mutation in the murine ortholog of CLN8 (7). In humans, the disease is characterized by juvenile progressive epilepsy with subsequent mental retardation; in the mouse model, by progressive degeneration of the motor system (7).
A number of human neurodegenerative diseases are characterized by oxidative damage (1, 2). Could it be possible that treatment with antioxidants could delay or halt further damage in such diseases? In this release of Physiological Genomics (Ref. 3; see page 195 in this release), researchers from the lab of Jeremy Nicholson use bioinformatics and "metabonomics" to determine whether dietary supplementation of the antioxidant vitamin E has any effect upon progression of neurodegeneration in the mnd model. Griffin et al. hypothesized that dietary supplementation of vitamin E might alter the pathology observed in mutant mice.
Control and experimental mice were fed one of three diets: standard, plus 10 times the normal level of vitamin E, or plus vitamin E, vitamin C, and selenium. Brain tissue and sera were collected for biochemical and metabolic assays using 1H-NMR spectroscopy. Principal component analysis was performed upon the data from the 1H-NMR spectra to identify metabolite changes between experimental groups. At baseline, there are a number of differences between control and mnd mice. First, cerebral tissue and blood plasma from mutant mice has a lower concentration of vitamin E than wild-type animals. Second, mnd mice have higher lipid levels than normal mice, implying an error in production of mitochondrial-associated membranes (MAMs) associated with lipid metabolism. Additionally, phenylalanine was found in cerebral tissue of mnd mice along with higher concentrations of lactate, glutamate, and N-acetyl aspartic acid (NAA) than wild-type controls.
Although dietary supplementation with vitamin E succeeded in reversing the vitamin deficiency in the mutant mice, it corrected neither the abnormal histological appearance of the brain nor the metabolic abnormalities caused by the genetic disorder. Brain tissue from treated mice retained the characteristic inclusion bodies of neuronal ceroid lipofuscinosis. Metabolic profiling revealed that mutants fed vitamin E (diet 2) had a lower concentration of serum unsaturated fatty acids than wild-type mice, but that the perturbed metabolic profiles observed at baseline were not otherwise significantly altered by feeding antioxidants.
Long-term antioxidant supplementation with vitamin E and sodium selenite has been given to patients with juvenile onset NCL (Batten-Spielmeyer-Vogt disease) with no clear improvement in the clinical course of the disease (8). Hematopoietic stem cell transplantation has been tried as a treatment for the infantile form of NCL (PPT1 enzyme deficiency) with only transient amelioration of the classic symptoms of the disease (5). Further cellular biological studies are needed to better understand the function of the defective proteins underlying NCL in order to design additional clinical trials for these disorders.
FOOTNOTES
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).
Address for reprint requests and other correspondence: I. Järvelä, Helsinki Univ. Central Hospital, Laboratory of Molecular Genetics, Obstetric Hospital, Haartmaninkatu 2, C-wing, 5th Floor, 00290 Helsinki, Finland (E-mail: rtx{at}sci.fi).
REFERENCES
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