Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease)

Bronson, Roderick T.; Lake, B. D.; Cook, Susan A.; Taylor, Susanne; Davisson, Muriel T.

doi:10.1002/ana.410330408

Cited by 143 publications

(76 citation statements)

References 26 publications

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“…For most of the spots the experimental molecular weight corresponded closely to the theoretical mass as deduced from the database. Only a few spots (20,29,31, 54, 57) indicated a lower molecular weight as compared to theoretical data, and one spot (49) exhibited a signi¢cantly higher experimental mass. Five spots were identi¢ed as hemoglobin chains probably representing blood contaminations during lipofuscin preparation.…”

Section: Resultsmentioning

confidence: 85%

Proteome analysis of lipofuscin in human retinal pigment epithelial cells

et al. 2002

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Excessive accumulation of lipofuscin in postmitotic retinal pigment epithelial cells is a common pathogenetic pathway in various blinding retinal diseases including age-related macular degeneration, which is now the most common cause of registerable blindness in the industrialized nations. To better understand the role of lipofuscin accumulation and to manipulate the pathogenetic mechanisms on both experimental and therapeutic levels we analyzed the proteome of isolated human ocular lipofuscin granules from human RPE cells. After homogenization and fractionation by gradient ultracentrifugation of the RPE/choroid complex from 10 pairs of human donors, protein compounds were separated by 2D gel electrophoresis and analyzed using matrix-assisted laser desorption/ionization mass spectrometry and HPLC-coupled electrospray tandem mass spectrometry. Besides a better understanding of downstream pathways, this approach may provide new targets for therapeutic interventions in a currently untreatable disease. ß

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Section: Resultsmentioning

confidence: 85%

Proteome analysis of lipofuscin in human retinal pigment epithelial cells

et al. 2002

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“…Together with the current study, genetic mouse models (two engineered and two naturally occurring) now exist for four of the eight forms of human NCL (19)(20)(21)(22)(23). Of these, the current model is among the most severe, with an onset clearly earlier than the CLN3 knockout (19,20), the nclf mouse [which likely represents a mouse model for NCL-6 (23)], and the mnd mouse [which represents NCL-8, or EPMR (progressive epilepsy with mental retardation) or ''Northern'' epilepsy] (22).…”

Section: Discussionmentioning

confidence: 96%

Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

Gupta

Soyombo

Atashband

et al. 2001

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

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PPT1 and PPT2 encode two lysosomal thioesterases that catalyze the hydrolysis of long chain fatty acyl CoAs. In addition to this function, PPT1 (palmitoyl-protein thioesterase 1) hydrolyzes fatty acids from modified cysteine residues in proteins that are undergoing degradation in the lysosome. PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis (also known as infantile Batten disease). In the current work, we engineered disruptions in the PPT1 and PPT2 genes to create ''knockout'' mice that were deficient in either enzyme. Both lines of mice were viable and fertile. However, both lines developed spasticity (a ''clasping'' phenotype) at a median age of 21 wk and 29 wk, respectively. Motor abnormalities progressed in the PPT1 knockout mice, leading to death by 10 mo of age. In contrast, the majority of PPT2 mice were alive at 12 mo. Myoclonic jerking and seizures were prominent in the PPT1 mice. Autofluorescent storage material was striking throughout the brains of both strains of mice. Neuronal loss and apoptosis were particularly prominent in PPT1-deficient brains. These studies provide a mouse model for infantile neuronal ceroid lipofuscinosis and further suggest that PPT2 serves a role in the brain that is not carried out by PPT1.

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“…The disease has also been described in cats [Greene and Little, 1974], cattle [Harper et al, 1988] goats [Fiske and Storts, 1988], monkeys [Jasty et al, 1984], and sheep, in which it has also been studied for many years [Palmer et al, 1989]. One murine form of NCL, motor neuron degeneration (mnd) [Bronson et al, 1993a], is located on proximal Chromosome 8 [Messer et al, 1992]. In this paper, we describe the genetics and pathology of a second mouse mutation, neuronal ceroid lipofuscinosis (nclf).…”

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confidence: 95%

“…This storage in neurons leads to, or is associated with, blindness, paralysis, and dementia. In the human late infantile NCL (CLN2, 11p15) [Sharp et al, 1997], juvenile NCL, and Batten disease (CLN3, 16p12.1), as well as in the canine, ovine, and murine forms, an abundant protein that accumulates in lysosomes is subunit c of mitochondrial F 1 F 0 -ATP synthase (gene symbol ATP5G, mouse gene symbol Atp5g) [Palmer et al, 1989;Fearnley et al, 1990;Hall et al, 1991;Palmer et al, 1992;Bronson et al, 1993a;Pardo et al, 1994]. A second similar proteolipid, processed vacuolar H + ATPase (ATP6C, mouse gene symbol Atp6c), has also been found to be stored in lysosomes of mice [Faust et al, 1994], dogs, sheep, and cattle with NCL (Brown et al, submitted for publication).…”

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confidence: 99%

Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9

et al. 1998

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The neuronal ceroid lipofuscinoses (NCLs) comprise a set of at least 6 distinct human and an unknown number of animal diseases characterized by storage of proteolipids in lysosomes of many cell types. By unknown mechanisms, this accumulation leads to or is associated with severe neuronal and retinal degeneration. The genes for 3 human NCLs, infantile, late infantile, and juvenile, have been cloned. The first murine form of NCL, the motor neuron degeneration (mnd) mouse, has been described and mapped to proximal Chromosome 8. Here we describe a second genetic variant of NCL in the mouse, neuronal ceroid lipofuscinosis, nclf. These mice exhibited a phenotype that was almost exactly the same as that observed in mnd/mnd mice. Homozygous nclf mice developed progressive retinal atrophy early in life and become paralyzed at around 9 months of age. They accumulated luxol fast blue staining material in cytoplasm of neurons and many other cell types. Ultrastructurally, affected lysosomes had a "finger print pattern" with membranous material arranged in "pentalaminar" patterns. Affected mice developed severe cerebral gliosis in late stages of their disease. They also had severe Wallerian degeneration of long tracts in spinal cord and brain stem, lesions that accounted for the distinctive upper motor neuron signs displayed by both nclf/nclf and mnd/mnd mice. By crossing nclf/nclf mice with CAST/Ei mice, linkage analysis of nclf with respect to SSLP markers was performed, showing that nclf is located on Chromosome 9 between D9Mit164 and D9Mit165, in a region that is homologous with human Ch 15q21, where the gene for one variant of late infantile NCL, CLN6, recently has been mapped. The genes for two proteolipids known to be stored in lysosomes of animals and people with NCL were also mapped in this study and found not to map to the mnd or nclf loci nor to any mouse locus homologous to any known human NCL disease locus.

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Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease)

Cited by 143 publications

References 26 publications

Proteome analysis of lipofuscin in human retinal pigment epithelial cells

Proteome analysis of lipofuscin in human retinal pigment epithelial cells

Disruption ofPPT1orPPT2causes neuronal ceroid lipofuscinosis in knockout mice

Neuronal ceroid lipofuscinosis (nclf), a new disorder of the mouse linked to chromosome 9

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