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

Gachet, Yannick; Codlin, Sandra; Hyams, Jeremy S.; Mole, Sara

doi:10.1242/jcs.02656

Cited by 73 publications

(113 citation statements)

References 73 publications

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“…Similarly helix 10 contains a conserved residue mutated in disease, and the loop between these helices 9 and 10 is very conserved suggesting that it should have the same orientation in yeast and mammalian species. Our assumption that conserved regions should have the same topological orientation is consistent with the knowledge that human CLN3 protein can functionally substitute for Btn1p in Schizosaccharomyces pombe and Saccharomyces cerevisiae [18,19]. CLN3 and its orthologues, then, have a topology that is not entirely straightforward to predict using currently available methods.…”

Section: Resultssupporting

confidence: 74%

“…Experimental interpretation to date has favoured the mammalian lysosome or yeast vacuole as the likely site of action, although there is evidence in Sz. pombe that Btn1p exerts a function from a prevacuolar compartment that affects vacuole homeostasis [18], and the same may be true for CLN3 in mammalian cells. In addition, CLN3 has been observed on the plasma membrane [14,16] in which case these domains would be projecting into the extracellular space until internalisation by endocytosis when they would regain a lumenal location.…”

Section: Resultsmentioning

confidence: 94%

“…This bias in frequency towards lumenal loops may be explained by the ability of glycosylation to prevent proteolysis in the protease-rich lysosomal lumen, thought to be the reason lysosomal membrane proteins are often heavily glycosylated. Both CLN3 and its yeast orthologues traffic to the lysosome/vacuole [13,18], although this may not be their only functional location. The remaining potential N-glycosylation motif has been placed within the first TM helix; however, unlike the other three, this site has not been validated experimentally and is most likely a false positive.…”

Section: Resultsmentioning

confidence: 99%

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The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data

2008

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The CLN3 gene encodes an integral membrane protein of unknown function. Mutations in CLN3 can cause juvenile neuronal ceroid lipofuscinosis, or Batten disease, an inherited neurodegenerative lysosomal storage disease affecting children. Here, we report a topological study of the CLN3 protein using bioinformatic approaches constrained by experimental data. Our results suggest that CLN3 has a six transmembrane helix topology with cytoplasmic N and C-termini, three large lumenal loops, one of which may contain an amphipathic helix, and one large cytoplasmic loop. Surprisingly, varied topological predictions were made using different subsets of orthologous sequences, highlighting the challenges still remaining for bioinformatics.

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data

2008

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“…By contrast, in btn1Δ cells, we observed a reduced number of punctae and the appearance of structures that were perinuclear and cortical, with ribbon-like connective tubules (Fig. 2B), typical of the S. pombe endoplasmic reticulum (ER) (Gachet et al, 2005;Pidoux and Armstrong, 1993;Vjestica et al, 2008) (supplementary material Fig. S1A).…”

Section: Deletion Of Btn1 Affects Vps10p Traffickingmentioning

confidence: 97%

“…Since Btn1p is involved in vacuole homeostasis in both S. pombe (Gachet et al, 2005) and S. cerevisiae (Kim et al, 2003;Pearce et al, 1999;Pearce and Sherman, 1998), and all NCL genes affect lysosomal function, with some encoding lysosomal hydrolases, we wondered whether Btn1p has a role in the trafficking of vacuolebound hydrolases. The best-studied vacuole protein-sorting (vps) pathway in yeasts is that of the hydrolase carboxypeptidase Y (Cpy1).…”

Section: Introductionmentioning

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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Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal, and synaptic compartments

Luiro

Kopra

Blom

et al. 2006

J of Neuroscience Research

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Intracellular pathways leading to neuronal degeneration are poorly understood in the juvenile neuronal ceroid lipofuscinosis (JNCL, Batten disease), caused by mutations in the CLN3 gene. To elucidate the early pathology, we carried out comparative global transcript profiling of the embryonic, primary cultures of the Cln3-/- mouse neurons. Statistical and functional analyses delineated three major cellular pathways or compartments affected: mitochondrial glucose metabolism, cytoskeleton, and synaptosome. Further functional studies showed a slight mitochondrial dysfunction and abnormalities in the microtubule cytoskeleton plus-end components. Synaptic dysfunction was also indicated by the pathway analysis, and by the gross upregulation of the G protein beta 1 subunit, known to regulate synaptic transmission via the voltage-gated calcium channels. Intracellular calcium imaging showed a delay in the recovery from depolarization in the Cln3-/- neurons, when the N-type Ca2+ channels had been blocked. The data suggests a link between the mitochondrial dysfunction and cytoskeleton-mediated presynaptic inhibition, thus providing a foundation for further investigation of the disease mechanism underlying JNCL disease.

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

Cited by 73 publications

References 73 publications

The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data

The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data

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

Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal, and synaptic compartments

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