CLN3 Protein Regulates Lysosomal pH and Alters Intracellular Processing of Alzheimer's Amyloid-β Protein Precursor and Cathepsin D in Human Cells

Golabek, Adam A.; Kida, E; Walus, Mariusz; Kaczmarski, Wojciech; Michalewski, Martin P.; Wisniewski, Krystyna E.

doi:10.1006/mgme.2000.3006

Cited by 101 publications

(70 citation statements)

References 38 publications

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“…This is opposite to that reported for btn1⌬ strains of budding yeast (Pearce, et al, 1998), and CLN3 overexpression studies in HEK293 cells (Golabek et al, 2000), but in agreement with observations made in cells from most types of NCL, including JNCL (Holopainen et al, 2001), supporting the use of fission yeast as a model for Batten disease. Our observation that the severity of mutations in Btn1p that mimicked those causing JNCL correlated with the increased vacuole pH further supports the use of fission yeast as a model for Batten disease.…”

Section: Btn1p Is the Functional Homologue Of Cln3supporting

confidence: 68%

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

Gachet

Codlin

Hyams

et al. 2005

Journal of Cell Science

100

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Section: Btn1p Is the Functional Homologue Of Cln3supporting

confidence: 68%

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

Gachet

Codlin

Hyams

et al. 2005

Journal of Cell Science

100

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“…A recent report indicates that, similar to yeast cells, arginine transport into lysosomes is defective in JNCL patient-derived lymphoblasts (Ramirez-Montealegre and . Other studies with human fibroblasts indicate CLN3 involvement in lysosomal pH maintenance and degradation (Golabek et al, 2000) and endocytosis (Luiro et al, 2004). Cells derived from Cln3 ⌬ex7/8 mice display defects in endosome-to-lysosome vesicular trafficking and mitochondrial function (Fossale et al, 2004), and microarray analysis of neurons from Cln3 ⌬ex7/8 mice reveals altered levels of transcripts coding for proteins involved in synaptic, cytoskeletal, and metabolic functions (Luiro et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

A Knock-In Reporter Model of Batten Disease

Eliason¹,

Stein²,

Mao³

et al. 2007

J. Neurosci.

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Juvenile neuronal ceroid lipofuscinosis is a severe inherited neurodegenerative disease resulting from mutations in CLN3 (ceroidlipofuscinosis, neuronal 3, juvenile). CLN3 function, and where and when it is expressed during development, is not known. In this study, we generated a knock-in reporter mouse to elucidate CLN3 expression during embryogenesis and after birth and to correlate expression and behavior in a CLN3-deficient mouse. In embryonic brain, expression appeared in the cortical plate. In postnatal brain, expression was prominent in the cortex, subiculum, parasubiculum, granule neurons of the dentate gyrus, and some brainstem nuclei. In adult brain, reporter gene expression waned in most areas but remained in vascular endothelia and the dentate gyrus. Mice homozygous for Cln3 deletion showed two hallmark pathological features of the neuronal ceroid lipofuscinosises: autofluorescent inclusions and lysosomal enzyme elevation. Moreover, CLN3-deficient reporter mice displayed progressive neurological deficits, including impaired motor function, decreased overall activity, acquisition of resting tremors, and increased susceptibility to pentilentetrazole-induced seizures. Notably, seizure induction in heterozygous mice was accompanied by enhanced reporter expression. This model provides us with the unique ability to correlate expression with pathology and behavior, thus facilitating the elucidation of CLN3 function and the pathogenesis of Batten disease.

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“…Trafficking defects arising from CLN3 dysfunction might underlie other clinically significant phenotypic effects. For example, aberrant processing of amyloid precursor protein (APP) in neurons, a hallmark for Alzheimer's disease, also reported in JNCL (Golabek et al, 2000;Kitaguchi et al, 1990;Villanova et al, 1999;Wisniewski et al, 1992;Wisniewski et al, 1990), could be explained by defective trafficking of the sortilin SORL1 (Andersen et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

S. pombe btn1, the orthologue of the Batten disease geneCLN3, is required for vacuole protein sorting of Cpy1p and Golgi exit of Vps10p

Codlin

Mole

2009

Journal of Cell Science

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Batten disease is characterised by lysosomal dysfunction. The most common type of the disease is caused by mutations in the membrane protein CLN3, whose function is unknown. We show that the fission yeast orthologue Btn1p, previously implicated in vacuole function, is required for correct sorting of the vacuole hydrolase carboxypeptidase Y (Cpy1p). This is, in part, due to a defect in trafficking of Vps10p, the sorting receptor for Cpy1p, from the Golgi to the trans-Golgi network in btn1Δ cells. Our data also implicate btn1 in other Vps10-independent Cpy1-sorting pathways. Furthermore, btn1 affects the number, intracellular location and structure of Golgi compartments. We show that the prevacuole location of Btn1p is at the Golgi, because Btn1p colocalises predominantly with the Golgi marker Gms1p in compartments that are sensitive to Brefeldin A. Btn1p function might be linked to that of Vps34p, a phosphatidylinositol 3-kinase, because Btn1p acts as a multicopy suppressor of the severe Cpy1p vacuole protein-sorting defect of vps34Δ cells. Together, these results indicate an important role for Btn1p in the Golgi complex, which affects Golgi homeostasis and vacuole protein sorting. We propose a similar role for CLN3 in mammalian cells.

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CLN3 Protein Regulates Lysosomal pH and Alters Intracellular Processing of Alzheimer's Amyloid-β Protein Precursor and Cathepsin D in Human Cells

Cited by 101 publications

References 38 publications

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

btn1, theSchizosaccharomyces pombehomologue of the human Batten disease geneCLN3, regulates vacuole homeostasis

A Knock-In Reporter Model of Batten Disease

S. pombe btn1, the orthologue of the Batten disease geneCLN3, is required for vacuole protein sorting of Cpy1p and Golgi exit of Vps10p

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