American Journal of Medical Genetics 42519-524 (1992)

Perspective of Biochemical Research in the Neuronal Ceroid-Lipofuscinosis ~

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J. Alfred Rider, Glyn Dawson, and Aristotle N. Siakotos Children’s Brain Diseases Foundation, San Francisco, California ( J A.R.); Department of Pediatrics, University of Chicago School of Medicine, Chicago (GD.);Department of Pathology, Indiana University School of Medicine, Indianapolis (A.N.S.)

The search for biochemical abnormalities in the neuronal ceroid-lipofuscinoses (NCL) or Batten disease was initiated with the discovery of normal levels of gangliosides in juvenile amaurotic idiocy. The primary goal of most biochemical studies has been to discover the unique biochemical marker for carriers and at-risk individuals. Ceroid, the singular pathomorphologic trait of NCL, was isolated and shown to differ from a similar but normal product of aged cells, lipofuscin. In spite of the availability of stored product, the chemical analysis of ceroid has not elucidated the unique biochemical defect in the NCL, as has been the case for other lysosomal storage disorders. The NCL were thought to be a result of lipid peroxidation because ceroid is also found in disorders of impaired vitamin E metabolism or results from a diet deficient in the antioxidant, vitamin E. In addition, tissue analysis indicated losses of polyunsaturated fatty acids in affecteds and carriers, as well as the presence of a secondary product of lipid peroxidation, 4-hydroxynonenal, in affected and carrier NCL dogs. With the exception of a fluorescent compound isolated from retinal ceroid, studies aimed at discovering the disease-specific fluorophores of ceroid have been largely inconclusive. The discovery of elevated dolichols in urine and brain tissue of NCL patients led to another hypothesis, that the basic biochemical defect in NCL involved the metabolism of dolichols and retinoids. However, the more recent view is that dolichol metabolism is secondaryto the unknown NCL lesion. A possible role of deficientproteasesor protease inhibitors in NCL was developed after studies showed that inhibition of lyso-

soma1thiol proteases would induce formation of autofluorescent lipopigments in brains of young rats. This initial discovery led to several reports of cathepsin deficiencies which, however, have not been reproducible. The discovery of abnormal storage of normal mitochondrial ATP synthase subunit C protein in NCL has been reported, but the reasons for the storage of this very hydrophobic protein were not apparent. A recent report found a modified amino acid, trimethyllysine in juvenile NCL ceroid. This may provide a reasonable explanation for the storage of the subunit C protein, i.e., the NCL defect may involve abnormal methylation and demethylation of proteins. Finally, localization of genes for 2 types of NCL mapping to 2 different chromosomes is a major advance in resolving the defect in NCL. Localization of genes for other inherited diseases has served as a prelude to the ultimate isolation and characterization of the genetic defect. With further progress in the biochemistry and molecular biology of NCL, the responsible gene product(s1 may soon be discovered and characterized.

KEY WORDS: Batten disease, biochemistry, peroxidation, dolichols, proteases, protein methylation

INTRODUCTION The neuronal ceroid-lipofuscinoses (NCL)or Batten disease, are a group of at least 4 clinical and pathological neurogenetic disorders. The disease usually affects children, but also appears in adults [Zeman and Siakotos, 1973; Zeman 19761. These conditions are characterized by the intracellular accumulation of autofluorescent lipopigment(s) (ceroid/lipofuscin),primarily in neurons, but also in other tissues. The 4 major types include the Received for publication July 9, 1991; revision received August infantile type (Santavouri-Haltia), late infantile (Jan27, 1991. Address reprint requests to J. Alfred Rider, M.D., Ph.D., Chil- sky-Bielschowsky),juvenile (Spielmeyer-Sjogren-Vogt), dren’s Brain Diseases Foundation, 350 Parnassus Avenue, Suite and adult onset types (Kufs [Berkovic A&BI) [Wisniewski et al., 1988; Boustany et al., 1988; Berkovic et 900, San Francisco, CA 94117. 0 1992 Wiley-Liss, Inc.

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al., 19881. All are characterized by progressive dementia, accompaniedby severe neuronal loss and brain atrophy (particularly in the infantile and late infantile forms). The different types of NCL frequently exhibit overlapping manifestations [Wisniewski et al., 19881. The frequency of NCL is estimated to be 1/12,500 live births, and with the protracted, progressive, fatal course of these disorders, NCL is a cause of great financial and social burden [Rider and Rider, 19883.

UNIQUE CHARACTERISTICS OF NCL In 1988 Rider and Rider presented a historical overview of the progress in the clinical diagnosis of the NCL. In that review much emphasis was placed on the diagnostic approach to NCL and the lack of a biochemical marker for the detection of carriers and at-risk individuals. Many reports present new findings suggesting various primary biochemical lesions in NCL. Nearly all of these promising initial observations were subsequently shown to have a secondary role in NCL, refuted or ignored as inconsequential. Therefore, the literature on NCL contains substantiated reports, descriptions of “primary” lesions reduced to a secondary role in the NCL pathology, or discoveries that are no longer considered reliable but have not been clearly refuted or withdrawn. This review will evaluate these discoveries and our current interpretation of them, so that investigators, new to NCL research, will be able to focus most effectively on the as yet undiscovered primary biochemical lesion. A major test for a pathogenetic enzyme deficiency is that carriers show levels of enzyme intermediate between those of normal and affected individuals. That is, affected persons will show gene defects in both allelic copies while carriers have a defect in only one COPY.

LIPID PEROXIDATION The search for unique biochemical abnormalities in NCL started with the discovery by Klenk [19391of normal levels of ganglioside in juvenile amaurotic idiocy when compared to the abnormally high levels found in Tay-Sachs brain tissue. In 1968 a series of papers appeared which laid the foundation implicating lipid peroxidation. In the first of these reports Hagberg et al. [ 19681found significant decreases in brain phosphatidyl ethanolamine polyunsaturated fatty acids (PUFA).The fatty acids that were reduced in concentration included docosahexaenoic acid (DHA) (22:6, w-31, docosatetraenoic acid (DTA)(22:4, w-61, and stearic acid. In contrast, Hagberg et al. [19681also reported an increase in arachidonic acid (20:4, w-6). Siakotos et al. [1974] isolated ceroid from NCL brain and showed that it could be separated from the age pigment (lipofuscin) in normal brain. Zeman [19711 proposed that the NCLs were a result of a deficiency in antioxidants or a loss of PUFA, presumably resulting in lipid peroxidation and the formation of ceroid. However, Siakotos et al. [19741 reported that plasma levels of alpha tocopherol, an antioxidant found in cell membranes, were normal in both human patients and carriers, as well as the English setter model of NCL. Armstrong et al. 119741reported a deficiency of p-phenylenediamine peroxidase in leuko-

cytes of patients with NCL. Currently the peroxidase deficiency theory is not favored in part, because the following enzymes are not abnormal in NCL: p-phenylenediamine peroxidase [Pilz et al., 1976a,b, 1978; Pronk and Koster, 19761, linoleyl hydroperoxide peroxidase [Schwerer and Bernheimer, 19781, phospholipid hydroperoxide glutathione, glutathione peroxidase, catalase, and superoxide dismutase [Marklund et al., 19811. A second report from Sweden [Svennerholm, 19751 on the loss of brain PUFA in NCL also appeared during this period, followedby studies by Pullarkat et al. [1978] indicating decreases in DHA in leukocyte phosphatidyl serine of NCL patients. Brain phosphatidyl serine showed a 35-90% reduction in DHA content in various forms of NCL [Pullarkat et al., 19821. In the infantile and late infantile forms of the disease increases in arachidonic acid were observed. Reddy et al. [1985a,bl reported a decrease in the DHA content of phosphatidyl ethanolamine in the English setter NCL retina. Paralled with the decrease in DHA, an increase in arachidonic acid was reported. In contrast, retinal pigment epithelium phosphatidyl ethanolamine from affected dogs had higher levels of DHA and lower levels of arachidonic acid. The metabolism of arachidonic acid was altered in canine NCL brain, microsomes, as evidenced by a decrease of 10-30% in long chain acyl coenzyme A synthetase [Reddyet al., 1985a,bl.This observation may be a consequence of the impaired turnover of membrane phospholipids and result in the increased levels of free fatty acids in NCL observed by Banerjee et al. [19911. The detection and identification of PUFA peroxidation products, such as fatty acyl hydroperoxides,has not been made with human NCL tissues. However, in the English setter NCL, Reddy et al. [1985a,bl reported a 31%increase in the synthesis of a lipoxygenase product of DHA, ( 11-hydroxy-4,7,9(trans)l3,16,19) DHA, when compared to normal retina, but no biosynthetic differences were observed in the pigment epithelium. Later, secondary products of lipid peroxidation, such as the 4-hydroxyunsaturated aldehydes, were reported to be elevated in neutrophils and tissues from affected and carrier NCL dogs [Siakotos et al., 19891. In addition, Dawson et al. [19901proposed that there is a lysosomal phospholipase (probably phospholipase A,) deficiency in brain homogenates and blood platelets from dogs affected with NCL. Normally, membrane phospholipids which have undergone peroxidation of their polyunsaturated fatty acid moiety require that the fatty acid hydroperoxides be excised as part of a normal repair mechanism by phospholipase A2.The free fatty acid peroxides are reduced to alcohols by glutathione peroxidase, and repair is completed by reacylation of the lysophospholipid with long chain fatty acyl coenzyme A acylase [van Kuijk et al., 19851. A deficiency of phospholipase A, or A, in a specific organelle, for example, a lysosome,would lead to accumulation of oxidized phospholipid in that organelle and its chemical degradation to toxic 4-hydroxyalkenals, such as 4-hydroxynonenal (HNE) [Esterbauer et al., 1986al. HNE was shown to be a potent inhibitor of thiol proteases [Dawson and Glaser, 19881 (as in leupeptin (see section on protease deficiencies)and

Biochemical Research in NCL could result in the accumulation of peptides seen in the NCL storage bodies.

NCL-SPECIFIC FLUOROPHORES The nature of the fluorophores in the NCL-specific autofluorescent lipopigment, ceroid, has been studied to identify disease-specificcompounds unique to these disorders [Katz et al., 19881.These studies have focused on the lipid-soluble fluorophores (soluble in lipid solvents, e.g., chlorofordmethanol) and protein-linked fluorophors (released from the lipid free pigment residue by acid or base hydrolysis). The lipid-like fluorophoreshave been shown to be unreliable as disease-specific indicators, primarily because they cannot be resolved from similar compounds found in tissues from normal controls. In marked contrast Katz and Rodrigues [19911 have recently shown the presence of a protein-bound disease specificcompound in retinal ceroid isolated from a juvenile NCL patient. Similar studies on storage bodies isolated from juvenile NCL brain and a normal control were inconclusivebecause of the large number of interfering components derived from lipofuscin or age pigment in normal brain. DOLICHOLS (POLYISOPRENOLS) Wolfe et al. [19771 reported retinoyl compounds in NCL ceroid and he proposed a prophylactic vitamin A-deficient diet for NCL patients. Later, the substance was actually shown to be dolichol [Goebel et al., 19791 and subsequently, Wolfe and Ng Yin Kim [19821 proposed that NCL was caused by a defect in dolichol metabolism. Wolfe et al. [1986] further showed that patients with NCL exhibit elevated urinary dolichol levels, as well as increased dolichol storage in brain. A study of dolichol levels indicated that false-negative results were obtained in 7.5%-15% of patients with NCL, while false positives were seen in 8.2-14.3% of patients with other neurological diseases, as well as with 15.4% of normal controls. Most important, the abnormal levels of urinary dolichol were not useful in carrier detection. Currently, the role of dolichols in NCL can be considered as secondary. PHOSPHORYLATED DOLICHOLS AND DOLICHYL PYROPHOSPHORYLOLIGOSACCARIDES Phosphorylated dolichols are increased in each human form of NCL [Keller et al., 1984; Hall and Patrick, 1985, 1988; Pullarkat et al., 1988; Wolfe et al., 19881. The changes in free dolichol are modest compared to the accumulation of the various phosphorylated dolichols. Phosphorylated dolichols also accumulate in ceroid in NCL. These changes are not exclusively seen in NCL but also occur in aging brain and with other pathological conditions.In addition dolichol pyrophosphoryloligosaccharides (predominantly Dol-PP-GlcNAc2-Man5-,,and Dol-PP-GlcNAc,-Man,-Glc,), accumulate up to 7%of the dry weight of the storage granules [Hall et al., 19911. Pullarkat et al. [19911 reported that some (but not all) JNCL patients showed a deficiency of endo-pN-acetylglucosaminidase-1,which could cause the accumulation of these dolichols and also result in abnormal

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glycoprotein breakdown (see below).Daniel et al. [19911, on the other hand, has proposed a specific lesion in an enzyme regulating the biosynthesis and/or utilization of lipid-linked oligosaccharide.

PROTEASES AND PROTEASE INHIBITORS Ivy et al. [19841presentedevidence that the inhibition of lysosomal thiol proteases would induce the formation of autofluorescent lipopigment in normal rat brain. Since then a number of lysosomal thiol proteases (cathepsins) have been investigated in NCL. Dawson and Glaser [19871 showed that apparent cathepsin-B deficiencies in NCL fibroblast cells, grown to very high passage number or normal cells exposed to low concentrations of hydrogen peroxide, resulted in a cathepsin-B deficiency, while cathepsin H remained normal. A cathepsin H deficiency in late infantile and juvenile NCL fibroblast cells and brain tissue was reported by Wolfe and Apannna [19891. However, Wolfe [19901 on reinvestigation of the Cathepsin H report, was not able to substantiate these findings. PROTEIN, PEPTIDE, GLYCOPROTEIN ABNORMALITIES IN NCL Wisniewski and Malinska [19891have described a 31 kDa preamyloid peptide that accumulates in NCL brain tissue. This peptide is also found in Alzheimer disease and neurons containing age pigment. In addition, Wisniewski and Kida [19901 have shown that alpha-1 antichymotrypsin is elevated in NCL brain tissue. Other changes observed in brain include 180 kDa glycoproteins which decrease in NCL brain tissue. The apparent storage of a mitochondrial ATP synthase subunit C in NCL has been reported by Palmer et al. [1989]. This protein is very hydrophobic (it is the lipid binding subunit) and accounts for about 40-70% of the material in isolated storage bodies. The subunit C is found in all types of NCL except the infantile disorder. In addition, the amino acid sequence has been reported to be normal without evidence for abnormally modified amino acids [Fearnley et al., 19901. Because the subunit C is very hydrophobic, this normal lipophilic material may be redistributed during tissue homogenization and purification of ceroid. Nevertheless, a number of questions remain: is the storage a result of over production of subunit C or a defect in the metabolism of subunit C? In ovine NCL the 2 structural genes for subunit C have normal sequences and m-RNA levels are also normal [Fearnley et al., 19901. Further, there does not appear to be any evidence for an abnormality in mitochondrial function or morphology. The remaining hypothesis is that NCL involves a defect in catabolism of subunit C [Fearnley et al., 19901,most probably a specificprotease, and that some specific mechanism is required for degrading this exceptionally hydrophobic protein. In contrast to Fearnley et al. 119901,Katz and Gerhardt 119903 found methylated methionine in late-infantile NCL storage bodies: Katz and Rodriques [19911has detected a modified amino acid, trimethyllysine, which is not present in control individuals, in juvenile NCL storage body protein.

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other sources of peroxides, such as cycloxygenation and agonist induced activation of blood cells, may also be important. The specificity of HNE and peroxides as inhibitors of cathepsin B and other sulfhydryl enzymes suggests one mechanism for altering the normal intracellular lysosomal catabolic process for proteins. In addition, aldehydes have been shown to go on to form fluorescent chromolipids similar to ceroid [Esterbauer et al., 1986bl. A disease-specific protein-bound autofluorescent compound has also been isolated by Katz and Rodrigues [1991] in juvenile retinal storage body proteins. Another area to be resolved is the accumulation of a normal mitochondria1 component, ATP synthase subunit C in NCL. Although Fearnley et al. [19901 claim that the storage body subunit C in NCL has a normal amino acid sequence, Katz and Gerhardt [19901discovered a modified amino acid, trimethyllysine, in NCL storage body protein isolated from juvenile retina and brain. In view of the fact that the 2 structural genes for subunit C show normal sequences and mRNA levels are normal [Palmer et al., 19901,it is difficult to understand why this apparently normal protein accumulates abnormally in this lysosomal disorder, unless there is a deficient subunit C specific protease. The appearance of a 31 kDa preamyloid peptide in NCL, as well as alpha-lchymotrypsin abnormalities, points to a derrangement, either primary in proteases or secondary to the massive brain atrophy. The localization of genes for specific types of NCL to 2 different chromosomesis a major advance in elucidating the cause of the NCL. Probably one or more other NCL CONCLUSIONS phenotypes will be shown to be caused by different geThe genes for 2 of the 4 types of NCL have been netic lesions. Localization of genes for other inherited mapped to different human chromosomes, chromosome diseases have served as a prelude to the ultimate isola16 for juvenile NCL and chromosome 1for the infantile tion and characterization of these defective genes. or Finnish disorder. The genes of the remaining forms of NCL and the various subtypes of late infantile and adult REFERENCES onset diseases remain to be mapped. The altered protein Armstrong D, Dimmitt S, vanwormer DE (1974): Studies in Batten synthesized by the mapped genes has not been identidisease. I. Peroxidase deficiency in granulocytes. Arch Neurol fied, since the defective genes have not been cloned. 30~144-156. A spectrum of apparent biochemical defects has been Banerjee P, Dasgupta A, Siakotos AN, Dawson G (1991):Evidence for implicated in these disorders, but many of these biolipase abnormality: High levels of unsaturated fatty acids in neuronal ceriod lipofuscinosis tissue. Am J Med Genet (in press). chemical changes are no longer regarded as useful in detecting affected but asymptomatic individuals, car- Berkovic SF, Carpenter S, Andermann F, Andermann E, Wolfe LS (1988): Kufs disease: a critical reappraisal. Brain 111:27-62. riers or even normals in a highly reproducible manner. Boustany RM, Ahoy J, Kolodny EH (1988): Clinical classification of The central nervous system is the main focus of the neuronal ceroid-lipofuscinosis subtypes. Am J Med Genet “Suppll pathogenetic defect. The reason for this brain-specific 5:47-58. abnormality probably is related to a biochemical event Daniel PF, Sauls DL, Boustany RM (1981): Abnormal dolichol metabolism in patients with neuronal ceroid-lipofuscinosis. Am J Med unique to brain. Genet (in press). It must be emphasized that some abnormalities, such Dawson G, Dawson SA, Siakotos AN (1990): Phospholipases and the as dolichol storage or excretion, are of value in diagnosis, molecular basis for the formation of ceroid in Batten disease. Adv but are probably secondary to the basic disease process. Exp Biol Med 266:259-271. Lipid peroxidation has been regarded as central to this Dawson G, Glaser P (1987):Apparent cathepsin B deficiency in neurogroup of disorders. The loss of essential PUFA in both nal ceroid-lipofuscinosis can be explained by peroxide inhibition. Biochem Biophys Res Commun 147:267-274. affected individuals and carriers implies a role for lipids, as do the abnormal amounts of secondary lipid peroxida- Dawson G, Glaser PT (1988): Abnormal cathepsin B activity in Batten disease. Am J Med Genet [Suppll 5:209-220. tion products, such as 4-hydroxyalkenals, detected in Eiberg H, Gardiner RM, Mohr J (1989): Batten disease (Spielmeyeraffected and carrier NCL dogs. The source of HNE has Sjogren disease) and haptoglobins (HP): indication of linkage and been presumed to be peroxidized phospholipids; howassignment to chromosome 16. Clin Genet 36:217-218. ever, Reddy at al. [1985a,bl have reported higher than Esterbauer H, Benedetti A, Lang J, Fulceri R, Fauler G, Comporti M (1986a): Studies on the mechanism of formation of 4-hydroxynonenormal rates of lipoxygenation in canine NCL. Probably

CHROMOSOMAL LOCALIZATION OF THE NCL GENES Family studies linking the defective genes in infantile and juvenile NCL to known markers have placed the genes for these disorders on chromosomes 1[Jarvella et al., 19911and 16 [Gardiner et al., 1990;Gardiner, 19911, respectively. Fkstriction fragment length polymorphism (RFLP) studies on 23 informative families have led to the conclusion that the gene for the most common (juvenile)form of NCL (CLN3) is linked to the haptoglobin locus on 16q [Eiberg et al., 19891. The most likely location of the CLN3 gene is near the D16S148locus (onlyone recombinant has been observed so far). No evidence for locus heterogeneity was seen among these families, but a candidate gene has not yet been proposed. The gene for another form of NCL, the Finnish infantile type (CLNl),was localized to the short arm of chromosome 1[Jarvella et al., 19911.A lod score of 4.0 (8 = 0) was reported, and a tentative localization between DlS57 and DlS79 was suggested. There was no evidence of heterogeneity among these families. Thus the infantile andjuvenile forms of NCL either involve different proteins or a protein with 2 subunits each coded by genes on different chromosomes, as previously found for lysosomal hydrolases such as p-hexosaminidase. The gene for the late infantile form of NCL (CLN2) has not yet been localized. Although CLN2 could be allelic either to CLN3 or CLN1, a third locus cannot be ruled out.

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Perspective of biochemical research in the neuronal ceroid-lipofuscinosis.

The search for biochemical abnormalities in the neuronal ceroid-lipofuscinoses (NCL) or Batten disease was initiated with the discovery of normal leve...
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