Progress in Neuropathology of the Neuronal Ceroid Lipofuscinoses

Goebel, Hans H.; Schochet, Sydney S.; Jaynes, Margaret; Brück, Wolfgang; Kohlschütter, Alfried; Hentati, Fayçal

doi:10.1006/mgme.1999.2808

Cited by 31 publications

(21 citation statements)

References 20 publications

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“…Immunohistochemical staining for the glial cell marker GFAP in brain and spinal cord sections revealed substantial gliosis in cat F Ϫ/Ϫ mice compared to agematched WT controls (Fig. 4B), which indicates neuronal stress or neurodegeneration (9) and which occurs in NCL patients and mouse models (21,38). Quantification of GFAP staining in four matched regions of the cortex and spinal cord demonstrated an average of ϳ6.7-fold increase in gliosis in cat (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Thus far, there has been little insight into the possible pathobiology of adult-onset NCL, although a few cases are caused by mild mutations of the PPT1 gene (39), and known NCL genes have been excluded by sequencing in some patients (S. E. Mole, unpublished data). The heterogeneity of clinical presentations of late-onset disease suggests that more than one gene is likely involved (9). Several naturally occurring animal models exist that appear to represent late-onset NCLs, but thus far the underlying genetic defects have also not been identified in these (5,27,30,34).…”

Section: Discussionmentioning

confidence: 99%

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Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Tang

Lee

Galvez

et al. 2006

Molecular and Cellular Biology

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Cathepsin F (cat F) is a widely expressed lysosomal cysteine protease whose in vivo role is unknown. To address this issue, mice deficient in cat F were generated via homologous recombination. Although cat F−/− mice appeared healthy and reproduced normally, they developed progressive hind leg weakness and decline in motor coordination at 12 to 16 months of age, followed by significant weight loss and death within 6 months. cat F was found to be expressed throughout the central nervous system (CNS). cat F−/− neurons accumulated eosinophilic granules that had features typical of lysosomal lipofuscin by electron microscopy. Large amounts of autofluorescent lipofuscin, characteristic of the neurodegenerative disease neuronal ceroid lipofuscinosis (NCL), accumulated throughout the CNS but not in visceral organs, beginning as early as 6 weeks of age. Pronounced gliosis, an indicator of neuronal stress and neurodegeneration, was also apparent in older cat F−/− mice. cat F is the only cysteine cathepsin whose inactivation alone causes a lysosomal storage defect and progressive neurological features in mice. The late onset suggests that this gene may be a candidate for adult-onset NCL.

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Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Tang

Lee

Galvez

et al. 2006

Molecular and Cellular Biology

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“…The NCL share clinical manifestations, biochemistry, and pathology, hence their classification together (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). It is probable that all of the NCL genes belong to a common metabolic pathway (15).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Ceroid Lipofuscinosis: A Common Pathway?

et al. 2007

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ABSTRACT:The neuronal ceroid lipofuscinoses are pediatric neurodegenerative diseases with common clinical features. Of the nine clinical variants (CLN1-CLN9), six have been genetically identified. Most variants manifest cell death and dysregulated sphingolipid metabolism, suggesting the proteins defective in these disorders may interact along one pathway. NCL patientderived cell lines exhibit cell growth and apoptotic defects that reverse following transfection with the wild-type gene. The membrane-bound proteins CLN3, CLN6, and CLN8 complement each other, as do CLN1 and CLN2 proteins, with respect to growth and apoptosis. The CLN2 protein also corrects growth and apoptosis in CLN3-, CLN6-, and CLN8-deficient cell lines. Neither CLN1-deficient nor CLN2-deficient growth defects are corrected by CLN3, CLN6, and CLN8 proteins. CLN2, CLN3, CLN6, and CLN8 proteins co-immunoprecipitate and co-localize to early and/or recycling endosomes and lipid rafts. Additionally, CLN2p and CLN1p co-immunoprecipitate. The work presented supports interactions between NCL proteins occurring at multiple points along one pathway. (Pediatr Res 61: 146-152, 2007)

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“…The clinical features include loss of vision, seizures, and mental and motor deterioration. Depending on the affected gene, the clinical signs become visible at various developmental stages (1). Currently, eight forms of human NCLs (CLN1-8) can be differentiated for which six underlying genes have been identified (2).…”

mentioning

confidence: 99%

Defective Endoplasmic Reticulum-resident Membrane Protein CLN6 Affects Lysosomal Degradation of Endocytosed Arylsulfatase A

Heine

Koch

Storch

et al. 2004

Journal of Biological Chemistry

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Variant late infantile neuronal ceroid lipofuscinosis, a lysosomal storage disorder characterized by progressive mental deterioration and blindness, is caused by mutations in a polytopic membrane protein (CLN6) with unknown intracellular localization and function. In this study, transient transfection of BHK21 cells with CLN6 cDNA and immunoblot analysis using peptide-specific CLN6 antibodies demonstrated the expression of a ϳ27-kDa protein that does not undergo proteolytic processing. Cross-linking experiments revealed the presence of CLN6 dimers. Using double immunofluorescence microscopy, epitope-tagged CLN6 was shown to be retained in the endoplasmic reticulum (ER) with no colocalization with the cis-Golgi or lysosomal markers. The translocation into the ER and proper folding were confirmed by the N-linked glycosylation of a mutant CLN6 polypeptide. Pulse-chase labeling of fibroblasts from CLN6 patients and from sheep (OCL6) and mouse (nclf) models of the disease followed by immunoprecipitation of cathepsin D indicated that neither the synthesis, sorting nor the proteolytic processing of this lysosomal enzyme was affected in CLN6-defective cells. However, the degradation of the endocytosed index protein arylsulfatase A was strongly reduced in all of the mutant CLN6 cell lines compared with controls. These data suggest that defects in the ER-resident CLN6 protein lead to lysosomal dysfunctions, which may result in lysosomal accumulation of storage material.

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Progress in Neuropathology of the Neuronal Ceroid Lipofuscinoses

Cited by 31 publications

References 20 publications

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

Neuronal Ceroid Lipofuscinosis: A Common Pathway?

Defective Endoplasmic Reticulum-resident Membrane Protein CLN6 Affects Lysosomal Degradation of Endocytosed Arylsulfatase A

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