Storage of saposins A and D in infantile neuronal ceroid‐lipofuscinosis

Tyynelä, Jaana; Palmer, David N.; Baumann, Marc; Haltia, Matti

doi:10.1016/0014-5793(93)80908-d

Cited by 168 publications

(102 citation statements)

References 49 publications

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“…In all types of NCL that have been characterized to date, the storage bodies have been reported to contain predominantly a single protein or a few major proteins: F 0 subunit c of mitochondrial ATP synthase, vacuolar V 0 ATPase subunit c, or saposins A and D (Palmer et al 1986(Palmer et al , 1989(Palmer et al , 1990(Palmer et al , 1997Tyynela et al 1993Tyynela et al , 1997a. Additional proteins are variably associated with the isolated storage bodies, but these have not been well characterized.…”

Section: Discussionmentioning

confidence: 99%

“…A distinctive feature of the NCLs is that the stored material contains predominantly a single protein or relatively few specific proteins (Haltia 2006;Palmer et al 1986Palmer et al , 1989Palmer et al , 1990Palmer et al , 1997Tyynela et al 1993Tyynela et al , 1997a. There are a number of different forms of human NCL that each result from mutations in one of at least eight different genes (PPT1, CLN2, CLN3, CLN5, CLN6, CLN8, CTSD and MFSD8) (Siintola et al 2006(Siintola et al , 2007Steinfeld et al 2006;Wisniewski et al 2001).…”

Section: Introductionmentioning

confidence: 99%

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Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

Katz

Sanders

Mooney

et al. 2007

J of Inher Metab Disea

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Summary The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases characterized by massive accumulation of autofluorescent storage bodies in neurons and other cells. A late‐onset form of NCL occurs in Tibetan terrier dogs. Gel electrophoretic analyses of isolated storage body proteins from brains of affected dogs indicated that a protein of approximately 50 kDa was consistently prominent and a 16 kDa component was present in some brain storage body preparations. Mass spectral analysis identified the 50 kDa protein as glial fibrillary acidic protein (GFAP), isoform 2. GFAP identification was supported by immunoblot and immunohistochemical analyses. Histone H4 was the major protein in the 16 kDa component. Specific accumulation of GFAP and histone H4 in storage bodies has not been previously reported for any of the NCLs. Tibetan terrier NCL may be the canine correlate of one of the human adult‐onset NCLs for which the genetic bases and storage body compositions have not yet been determined.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

Katz

Sanders

Mooney

et al. 2007

J of Inher Metab Disea

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“…Specific lysosomal storage of subunit c has been demonstrated by protein sequencing of bodies from these sheep and of human samples associated with the CLN2 (late infantile), CLN3 (juvenile), (14 -16), CLN5, and CLN8 human forms (17,18). They are not associated with the CLN1 (infantile) form (19). The stored protein and the normal mitochondrial subunit c were found to be identical by protein sequencing (15,16).…”

mentioning

confidence: 92%

Lysine 43 Is Trimethylated in Subunit c from Bovine Mitochondrial ATP Synthase and in Storage Bodies Associated with Batten Disease

Chen

Fearnley

Palmer

et al. 2004

Journal of Biological Chemistry

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The hydrophobic membrane protein, subunit c, has been isolated from ATP synthase purified from bovine heart mitochondria. It has also been obtained from lysosomal storage bodies associated with ceroid lipofuscinosis from ovine liver and from human brain tissue of a victim of Batten disease. It is likely that the lysosomal protein has originated from the mitochondrion. These samples have been characterized by mass spectrometric methods. Irrespective of its source, subunit c has an intact molecular mass of 7650 Da, 42 Da greater than the value calculated from the amino acid sequence, and the protein has been modified post-translationally. In all three samples, the modification is associated with lysine 43, which lies in a polar loop region linking the two transmembrane ␣-helices of the protein. This residue is conserved throughout vertebrate sequences. The additional mass arises from trimethylation and not acetylation at the ⑀-N-position of the residue. These experiments show that the post-translational modification of subunit c is not, as has been suggested, an abnormal phenomenon associated with the etiology of Batten disease and ceroid lipofucinoses. Evidently, it occurs either before or during import of the protein into mitochondria or at a mitochondrial location after completion of the import process. The function of the trimethyllysine residue in the assembled ATP synthase complex is obscure. The residue and the modification are not conserved in all ATP synthases, and their role in the assembly and (or) functioning of the enzyme appear to be confined to higher organisms.

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“…The intraneuronal deposits were autofluorescent and contained saposin D and subc of the mitochondrial ATP synthase. Both findings, as well as the morphology of storage material, are typical for human lysosomal storage diseases named NCL or sometimes Batten disease (25)(26)(27). NCL is a genetically and phenotypically heterogeneous group of progressive neurodegenerative disorders with at least eight subtypes (28).…”

Section: Ncl the Neurological Deficits Of Clcn6mentioning

confidence: 99%

Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6

Poët

Kornak

Schweizer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

170

221

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Mammalian CLC proteins function as Cl ؊ channels or as electrogenic Cl ؊ ͞H ؉ exchangers and are present in the plasma membrane and intracellular vesicles. We now show that the ClC-6 protein is almost exclusively expressed in neurons of the central and peripheral nervous systems, with a particularly high expression in dorsal root ganglia. ClC-6 colocalized with markers for late endosomes in neuronal cell bodies. The disruption of ClC-6 in mice reduced their pain sensitivity and caused moderate behavioral abnormalities. Neuronal tissues showed autofluorescence at initial axon segments. At these sites, electron microscopy revealed electron-dense storage material that caused a pathological enlargement of proximal axons. These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. However, the lysosomal pH of Clcn6 ؊/؊ neurons appeared normal. CLCN6 is a candidate gene for mild forms of human NCL. Analysis of 75 NCL patients identified ClC-6 amino acid exchanges in two patients but failed to prove a causative role of CLCN6 in that disease.acidification ͉ anion transport ͉ Batten disease ͉ channelopathy ͉ Kufs' disease

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Storage of saposins A and D in infantile neuronal ceroid‐lipofuscinosis

Cited by 168 publications

References 49 publications

Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

Lysine 43 Is Trimethylated in Subunit c from Bovine Mitochondrial ATP Synthase and in Storage Bodies Associated with Batten Disease

Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6

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