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next investigated the basis for subunit c accumulation, testing the hypothesis that cathepsin D is abnormal since it is required for ATP synthase subunit c degradation in the lysosome [13]. We first tested cathepsin D transport and processing in homozygous CbCln3Δex7/8 cells and Cln3Δex7/8 mice using anti-cathepsin D antibody that recognizes unprocessed and processed cathepsin D isoforms. Immunostaining of wild-type and homozygous CbCln3Δex7/8 cells revealed a perinuclear and punctate vesicular cathepsin D distribution, consistent with its transport and processing through the secretory pathway and delivery to the lysosome (Fig. 5a). However, in homozygous CbCln3Δex7/8 cells, cathepsin D distribution was less vesicular and more perinuclear-clustered than in wild-type cells. Immunoblots of homozygous CbCln3Δex7/8 cell and Cln3Δex7/8 tissue extracts also showed altered relative levels of cathepsin D isoforms (Fig. 5b). Cathepsin D isoforms, identified by relative molecular weights, represent the ~45 kDa precursor, the ~43 kDa intermediate single chain form of the enzyme, and the 31 kDa heavy chain of the double-chain form of the mature enzyme [14]. In homozygous CbCln3Δex7/8 cell and Cln3Δex7/8 tissue extracts, the precursor and heavy chains were reduced, and the single chain was slightly elevated compared to wild-type extracts. The cellular growth media did not contain altered levels of cathepsin D, indicating enzyme secretion was not affected. Heterozygous Cln3Δex7/8 mice and CbCln3Δex7/8 cells were indistinguishable from wild-type, as expected for a recessive disease phenotype (data not shown)."}

{"project":"craft-ca-core-ex-dev","denotations":[{"id":"T2427","span":{"begin":35,"end":44},"obj":"PR_EXT:000022190"},{"id":"T2428","span":{"begin":87,"end":98},"obj":"PR_EXT:000006025"},{"id":"T2429","span":{"begin":136,"end":139},"obj":"CHEBI_EXT:ATP"},{"id":"T2430","span":{"begin":136,"end":158},"obj":"PR_EXT:000022190"},{"id":"T2431","span":{"begin":178,"end":186},"obj":"GO:0005764"},{"id":"T2432","span":{"begin":209,"end":220},"obj":"PR_EXT:000006025"},{"id":"T2433","span":{"begin":221,"end":230},"obj":"GO_EXT:biological_routing_or_transport"},{"id":"T2434","span":{"begin":235,"end":245},"obj":"SO_EXT:sequence_alteration_process"},{"id":"T2435","span":{"begin":260,"end":262},"obj":"UBERON:0002037"},{"id":"T2436","span":{"begin":262,"end":266},"obj":"PR_EXT:000005591"},{"id":"T2437","span":{"begin":273,"end":278},"obj":"CL_GO_EXT:cell"},{"id":"T2438","span":{"begin":283,"end":287},"obj":"PR_EXT:000005591"},{"id":"T2439","span":{"begin":294,"end":298},"obj":"NCBITaxon:10088"},{"id":"T2440","span":{"begin":310,"end":321},"obj":"PR_EXT:000006025"},{"id":"T2441","span":{"begin":322,"end":330},"obj":"GO:0042571"},{"id":"T2442","span":{"begin":349,"end":358},"obj":"SO_EXT:sequence_alteration_process"},{"id":"T2443","span":{"begin":363,"end":372},"obj":"SO_EXT:sequence_alteration_process"},{"id":"T2477","span":{"begin":1080,"end":1086},"obj":"CHEBI_GO_SO_EXT:enzyme"},{"id":"T2478","span":{"begin":1122,"end":1134},"obj":"SO:0000985"},{"id":"T2479","span":{"begin":1154,"end":1160},"obj":"CHEBI_GO_SO_EXT:enzyme"},{"id":"T2480","span":{"begin":1181,"end":1183},"obj":"UBERON:0002037"},{"id":"T2481","span":{"begin":1183,"end":1187},"obj":"PR_EXT:000005591"},{"id":"T2482","span":{"begin":1194,"end":1198},"obj":"CL_GO_EXT:cell"},{"id":"T2483","span":{"begin":1203,"end":1207},"obj":"PR_EXT:000005591"},{"id":"T2484","span":{"begin":1214,"end":1220},"obj":"UBERON:0000479"},{"id":"T2485","span":{"begin":1331,"end":1340},"obj":"SO_EXT:wild_type_entity_or_quality"},{"id":"T2486","span":{"begin":1355,"end":1363},"obj":"CL_GO_EXT:cell"},{"id":"T2487","span":{"begin":1364,"end":1370},"obj":"GO_EXT:biological_growth_entity_or_process"},{"id":"T2488","span":{"begin":1411,"end":1422},"obj":"PR_EXT:000006025"},{"id":"T2489","span":{"begin":1435,"end":1441},"obj":"CHEBI_GO_SO_EXT:enzyme"},{"id":"T2490","span":{"begin":1442,"end":1451},"obj":"GO_EXT:secretion_entity_or_process"},{"id":"T2491","span":{"begin":1483,"end":1487},"obj":"PR_EXT:000005591"},{"id":"T2492","span":{"begin":1494,"end":1498},"obj":"NCBITaxon:10088"},{"id":"T2493","span":{"begin":1503,"end":1505},"obj":"UBERON:0002037"},{"id":"T2494","span":{"begin":1505,"end":1509},"obj":"PR_EXT:000005591"},{"id":"T2495","span":{"begin":1516,"end":1521},"obj":"CL_GO_EXT:cell"},{"id":"T2496","span":{"begin":1550,"end":1559},"obj":"SO_EXT:wild_type_entity_or_quality"},{"id":"T2444","span":{"begin":373,"end":384},"obj":"PR_EXT:000006025"},{"id":"T2445","span":{"begin":385,"end":393},"obj":"SO_EXT:0001060"},{"id":"T2446","span":{"begin":413,"end":422},"obj":"SO_EXT:wild_type_entity_or_quality"},{"id":"T2447","span":{"begin":438,"end":440},"obj":"UBERON:0002037"},{"id":"T2448","span":{"begin":440,"end":444},"obj":"PR_EXT:000005591"},{"id":"T2449","span":{"begin":451,"end":456},"obj":"CL_GO_EXT:cell"},{"id":"T2450","span":{"begin":472,"end":479},"obj":"GO:0005634"},{"id":"T2451","span":{"begin":493,"end":502},"obj":"GO:0031982"},{"id":"T2452","span":{"begin":503,"end":514},"obj":"PR_EXT:000006025"},{"id":"T2453","span":{"begin":549,"end":558},"obj":"GO_EXT:biological_routing_or_transport"},{"id":"T2454","span":{"begin":563,"end":573},"obj":"SO_EXT:sequence_alteration_process"},{"id":"T2455","span":{"begin":586,"end":603},"obj":"GO_EXT:secretory_pathway"},{"id":"T2456","span":{"begin":608,"end":616},"obj":"GO_EXT:biological_routing_or_transport"},{"id":"T2457","span":{"begin":624,"end":632},"obj":"GO:0005764"},{"id":"T2458","span":{"begin":667,"end":669},"obj":"UBERON:0002037"},{"id":"T2459","span":{"begin":669,"end":673},"obj":"PR_EXT:000005591"},{"id":"T2460","span":{"begin":680,"end":685},"obj":"CL_GO_EXT:cell"},{"id":"T2461","span":{"begin":687,"end":698},"obj":"PR_EXT:000006025"},{"id":"T2462","span":{"begin":721,"end":730},"obj":"GO:0031982"},{"id":"T2463","span":{"begin":744,"end":751},"obj":"GO:0005634"},{"id":"T2464","span":{"begin":770,"end":779},"obj":"SO_EXT:wild_type_entity_or_quality"},{"id":"T2465","span":{"begin":780,"end":785},"obj":"CL_GO_EXT:cell"},{"id":"T2466","span":{"begin":813,"end":815},"obj":"UBERON:0002037"},{"id":"T2467","span":{"begin":815,"end":819},"obj":"PR_EXT:000005591"},{"id":"T2468","span":{"begin":826,"end":830},"obj":"CL_GO_EXT:cell"},{"id":"T2469","span":{"begin":835,"end":839},"obj":"PR_EXT:000005591"},{"id":"T2470","span":{"begin":846,"end":852},"obj":"UBERON:0000479"},{"id":"T2471","span":{"begin":901,"end":912},"obj":"PR_EXT:000006025"},{"id":"T2472","span":{"begin":913,"end":921},"obj":"SO_EXT:0001060"},{"id":"T2473","span":{"begin":933,"end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next investigated the basis for subunit c accumulation, testing the hypothesis that cathepsin D is abnormal since it is required for ATP synthase subunit c degradation in the lysosome [13]. We first tested cathepsin D transport and processing in homozygous CbCln3Δex7/8 cells and Cln3Δex7/8 mice using anti-cathepsin D antibody that recognizes unprocessed and processed cathepsin D isoforms. Immunostaining of wild-type and homozygous CbCln3Δex7/8 cells revealed a perinuclear and punctate vesicular cathepsin D distribution, consistent with its transport and processing through the secretory pathway and delivery to the lysosome (Fig. 5a). However, in homozygous CbCln3Δex7/8 cells, cathepsin D distribution was less vesicular and more perinuclear-clustered than in wild-type cells. Immunoblots of homozygous CbCln3Δex7/8 cell and Cln3Δex7/8 tissue extracts also showed altered relative levels of cathepsin D isoforms (Fig. 5b). Cathepsin D isoforms, identified by relative molecular weights, represent the ~45 kDa precursor, the ~43 kDa intermediate single chain form of the enzyme, and the 31 kDa heavy chain of the double-chain form of the mature enzyme [14]. In homozygous CbCln3Δex7/8 cell and Cln3Δex7/8 tissue extracts, the precursor and heavy chains were reduced, and the single chain was slightly elevated compared to wild-type extracts. The cellular growth media did not contain altered levels of cathepsin D, indicating enzyme secretion was not affected. Heterozygous Cln3Δex7/8 mice and CbCln3Δex7/8 cells were indistinguishable from wild-type, as expected for a recessive disease phenotype (data not shown)."}

{"project":"2_test","denotations":[{"id":"15588329-12440525-12950144","span":{"begin":188,"end":190},"obj":"12440525"},{"id":"15588329-12350228-12950145","span":{"begin":1162,"end":1164},"obj":"12350228"}],"text":"We next investigated the basis for subunit c accumulation, testing the hypothesis that cathepsin D is abnormal since it is required for ATP synthase subunit c degradation in the lysosome [13]. We first tested cathepsin D transport and processing in homozygous CbCln3Δex7/8 cells and Cln3Δex7/8 mice using anti-cathepsin D antibody that recognizes unprocessed and processed cathepsin D isoforms. Immunostaining of wild-type and homozygous CbCln3Δex7/8 cells revealed a perinuclear and punctate vesicular cathepsin D distribution, consistent with its transport and processing through the secretory pathway and delivery to the lysosome (Fig. 5a). However, in homozygous CbCln3Δex7/8 cells, cathepsin D distribution was less vesicular and more perinuclear-clustered than in wild-type cells. Immunoblots of homozygous CbCln3Δex7/8 cell and Cln3Δex7/8 tissue extracts also showed altered relative levels of cathepsin D isoforms (Fig. 5b). Cathepsin D isoforms, identified by relative molecular weights, represent the ~45 kDa precursor, the ~43 kDa intermediate single chain form of the enzyme, and the 31 kDa heavy chain of the double-chain form of the mature enzyme [14]. In homozygous CbCln3Δex7/8 cell and Cln3Δex7/8 tissue extracts, the precursor and heavy chains were reduced, and the single chain was slightly elevated compared to wild-type extracts. The cellular growth media did not contain altered levels of cathepsin D, indicating enzyme secretion was not affected. Heterozygous Cln3Δex7/8 mice and CbCln3Δex7/8 cells were indistinguishable from wild-type, as expected for a recessive disease phenotype (data not shown)."}