count	source_label	source_id	relationship	target_label	target_id	entity_type	solr_id	publication_id	sentences
4	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:P03372	Protein	a37948e6-3909-11e8-a51f-001a4a160176	25987168	Examples of cargo delivery proteins include, Niemann Pick Type C1 protein, whose loss of function results in impaired delivery of late endosomal cargo to lysosomes and the ER[4], and Kuf's disease, a late-onset neuronal ceroid lipofuscinosis disease caused by mutations in the CLN6 gene, which encodes an ER-resident protein that maintains lysosomal function[5].
4		UNIPROT:P27824	inhibits	CLN6	UNIPROT:Q9NWW5	Protein	7e4b4e6a-aba8-11e6-9ac8-001a4ae51246	26073432	Whilst PDI is present in both control and CLN6−/−cultures, calnexin is significantly reduced in affected cells (Fig. 1), perhaps indicating a decrease in expression, or misprocessing or folding in the absence of functional CLN6.
4		FPLX:GSK3	activates	CLN6	UNIPROT:Q9NWW5	ProteinFamily	7e4b4e6a-aba8-11e6-9ac8-001a4ae51246	26073432	Increased zinc and manganese concentrations in parallel with neurodegeneration, synaptic protein changes and activation of Akt/GSK3 signalling in ovine CLN6 neuronal ceroid lipofuscinosis was reported[37].
4		FPLX:AKT	activates	CLN6	UNIPROT:Q9NWW5	ProteinFamily	7e4b4e6a-aba8-11e6-9ac8-001a4ae51246	26073432	Increased zinc and manganese concentrations in parallel with neurodegeneration, synaptic protein changes and activation of Akt/GSK3 signalling in ovine CLN6 neuronal ceroid lipofuscinosis was reported[37].
2	CLN6	UNIPROT:Q9NWW5	activates		MESH:D003911	Phenotype	c8780b9a-3905-11e8-8636-001a4a160175	28065762	Overexpression of CLN6 in affected cells caused a 129% increase in LysoTracker fluorescent intensity (0.62±0.22 CLN6−/−vs. 1.42±0.34 virus treated,Fig. 2A–C), a 31% increase in Cyto-ID fluorescence (0.80±0.16 CLN6−/−vs. 1.05±0.14 virus treated,Fig. 2F, G), and a 39% increase in fluorescent dextran intensity per cell (0.79±0.32 CLN6−/−vs. 1.15±0.14 virus treated,Fig. 2H, I).
2		UNIPROT:O43175	activates	CLN6	UNIPROT:Q9NWW5	Protein	d8a8a102-bc05-11e5-9b9d-001a4ae51247	10.1016/j.yexcr.2004.04.042	The sera enabled detection of CLN6 that had not been exposed to reducing agents nor excessively denatured by heat (data not shown).
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:P03372	Protein	d26f3f44-bc37-11e5-9b9d-001a4ae51247	PMC3335005	Thus, disruption of ER function caused by mutant Cln6 could interfere with the assembly of the autophagosomal membrane and subsequently block this pathway.
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:O43312	Protein	638dd902-bc4e-11e5-8d2d-001a4ae51247	10.1016/j.bbamcr.2008.11.004	CLN6 disease Mutations in theCLN6gene cause a variant late infantile neuronal ceroid lipofuscinosis (vLINCL;MIM#601780).
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:P07204	Protein	3e9c2f62-3407-11e8-8f56-001a4a160175	28476624	Aggregate positivity in CLN6-depleted cells was ∼25% higher than that in CLN6-sufficient counterparts (Fig. 2D), indicating that TMαBC's preventive effect on the R120G mutant is mediated, at least in part, by CLN6.
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:Q9H3Z4	Protein	cb3fd462-352b-11e8-8636-001a4a160175	27844444	However, the apparently heterogeneous adult-onset forms of NCL (Kufs disease) including CLN4 disease caused by mutations in DNAJC5 and adult CLN6 disease both lead to dementia without visual loss but have a much later age of onset than our patients [26].
1	CLN6	UNIPROT:Q9NWW5	increases		UNIPROT:P41440	Protein	219b64d0-bbd9-11e5-956b-001a4ae51247	PMC2947195	cl-N6/C6was co-transfected into hRFC-null R5 Hela cells to test for restoration of transport function and hRFC protein expression.wt-N6/C6was transfected in parallel as a positive control.
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:P19338	Protein	3869f146-bc32-11e5-9b9d-001a4ae51247	PMC3790850	The CLN6 gene encodes a transmembrane protein of unknown function and mutations cause the variant-late infantile form of NCL (vLINCL) as well as an adult form termed Kufs disease[9]–[11].
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:P19338	Protein	34b80a1e-ae94-11ec-ae7b-0050569a1f61	PMCPMC8640139	NCL caused by biallelic variants in the CLN6 gene usually presents in early to late childhood to juvenile, between 1.5 and 8 years of age, with slow motor degeneration, ataxia, loss of vision, seizures (epilepsy), and mental disabilities.
1	CLN6	UNIPROT:Q9NWW5	inhibits		UNIPROT:P19338	Protein	3bf138be-d153-11ec-99c8-0050569a791b	10.1371/journal.pone.0261544	However, intracerebroventricular delivery of CLN6 gene therapy to the neonatal Cln6 mutant mouse has been shown to prevent or drastically reduce all the pathological hallmarks of NCL, as well as improving behaviour and extending survival [38].
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:P19338	Protein	2386747c-ae96-11ec-b4ed-0050569a1f61	PMC8360550	The detection of CLN6-induced NCL has also been reported in some breeds of dogs, including Border Collies, English Setters, American Bulldogs, Dachshunds, and Australian Shepherds [57].
1	CLN6	UNIPROT:Q9NWW5	inhibits		UNIPROT:P19338	Protein	649d7226-8d85-11e7-bc62-001a4ae51247	PMC5611964	The maturation of neurons has previously been shown to be reduced in NCL caused by loss of the CLN6 protein (Benedict et al., 2009).
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:P19338	Protein	37836bbe-bbff-11e5-9b9d-001a4ae51247	PMC2758138	Mutations in the CLN6 gene, located on chromosome 15q23 (10,11), cause a variant late infantile form of NCL (vLINCL).
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:O75503	Protein	7ff00804-ae96-11ec-8b2e-0050569a1f61	PMC8195759	CLN6, an ER-resident NCL protein, regulates the correct transport of CLN5 to the lysosome, and loss of CLN6 disrupts transport of CLN5 [59].
1	CLN6	UNIPROT:Q9NWW5	activates		UNIPROT:Q9NWW5	Protein	c8780b9a-3905-11e8-8636-001a4a160175	28065762	Notably, overexpression of CLN6 also increased LysoTracker intensity in control cells (Fig. 2B, C), implicating CLN6 in the regulation of vesicle pH or lysosomal biogenesis.
1	CLN6	UNIPROT:Q9NWW5	inhibits		UNIPROT:Q92504	Protein	e313273a-bc40-11e5-ac4e-001a4ae51246	PMC3683166	Future studies will investigate how the loss of CLN6 may trigger changes in Zip7, and how this results in cellular biometal redistribution.
1	CLN6	UNIPROT:Q9NWW5	activates		GO:0006810	Phenotype	7ff00804-ae96-11ec-8b2e-0050569a1f61	PMC8195759	CLN6, an ER-resident NCL protein, regulates the correct transport of CLN5 to the lysosome, and loss of CLN6 disrupts transport of CLN5 [59].
1	CLN6	UNIPROT:Q9NWW5	activates		MESH:D059865	Phenotype	d26f3f44-bc37-11e5-9b9d-001a4ae51247	PMC3335005	These data suggest that the proteasomal degradation of mutant p.R103PfsX62 Cln6 is sufficient to prevent the accumulation of misfolded Cln6 protein and the subsequent activation of ER stress.
1	CLN6	UNIPROT:Q9NWW5	activates		MESH:D002784	Phenotype	bbacd362-bc09-11e5-9b9d-001a4ae51247	10.1016/j.bbadis.2013.01.019	It is not clear, how mutant CLN6 leads to lysosomal dysfunction characterized by accumulation of autofluorescent lipopigments, subunit c of mitochondrial ATP synthase, free cholesterol and phospho- and glycosphingolipids in lysosome-derived storage bodies[196–201].
1	CLN6	UNIPROT:Q9NWW5	inhibits		GO:0000184	Phenotype	bbacd362-bc09-11e5-9b9d-001a4ae51247	10.1016/j.bbadis.2013.01.019	The half-life of CLN6 was estimated to be >30h, whereas the rate of synthesis and the stability of mutant CLN6 proteins are reduced due to nonsense-mediated mRNA decay and proteasomal degradation, respectively[194–196].
1	CLN6	UNIPROT:Q9NWW5	inhibits		MESH:D018450	Phenotype	e313273a-bc40-11e5-ac4e-001a4ae51246	PMC3683166	These data indicate the tissues where maintenance of CLN6 expression may be required for physiological functions in motor and visual control, however, analysis of biochemical correlates is required to determine the functional outcomes of lowered CLN6 expression that may contribute to disease progression.
1	CLN6	UNIPROT:Q9NWW5	activates		MESH:D009472	Phenotype	638dd902-bc4e-11e5-8d2d-001a4ae51247	10.1016/j.bbamcr.2008.11.004	CLN6 disease Mutations in theCLN6gene cause a variant late infantile neuronal ceroid lipofuscinosis (vLINCL;MIM#601780).
1	CLN6	UNIPROT:Q9NWW5	activates		MESH:D009472	Phenotype	d3a53542-2856-11e9-aa64-001a4a160176	PMC6354087	Patients with variant late infantile neuronal ceroid lipofuscinosis caused by a mutation in the CLN6 gene have been reported in a number of countries worldwide, including in Costa Rica, Portugal, the Czech Republic, Sudan, Turkey, Saudi Arabia, Pakistan, and Japan[6-10].
1	CLN6	UNIPROT:Q9NWW5	inhibits		FPLX:Proteasome	ProteinFamily	7e24d6d6-c8eb-11e5-a4c6-001a4ae51246	PMC2674128	RESULTS Cln6 mutant molecules are stabilized by inclusion of proteasome inhibition Cln6 is a 311 amino acid non-glycosylated ER membrane protein that is predicted to contain either five or six transmembrane domains [12,14].
1		UNIPROT:P03372	activates	CLN6	UNIPROT:Q9NWW5	Protein	bbacd362-bc09-11e5-9b9d-001a4ae51247	10.1016/j.bbadis.2013.01.019	The N-terminal cytoplasmic 49 amino acids and the distal pair of transmembrane domains 6 and 7 contain combinatorial motifs for ER retention of CLN6[193].
1		FPLX:Proteasome	inhibits	CLN6	UNIPROT:Q9NWW5	ProteinFamily	7e24d6d6-c8eb-11e5-a4c6-001a4ae51246	PMC2674128	To examine whether the Cln6 mutants are degraded by the proteasome, Cln6 protein levels were examined from U373Cln6wt, U373Cln6G123Dand U373Cln6M241Tcells treated with or without the proteasome inhibitor ZL3VS (carboxybenzyl-leucyl-leucyl-leucyl vinyl sulfone) (10 μM) for 5 h [22].
1		UNIPROT:Q9UBV2	inhibits	CLN6	UNIPROT:Q9NWW5	Protein	7e24d6d6-c8eb-11e5-a4c6-001a4ae51246	PMC2674128	In addition, knockdown of SEL1L [sel-1 suppressor of lin-12-like (Caenorhabditis elegans)], a protein involved in the disposal of aberrant ER proteins, rescued the degradation of the Cln6 mutants.
1		UNIPROT:P07204	activates	CLN6	UNIPROT:Q9NWW5	Protein	3e9c2f62-3407-11e8-8f56-001a4a160175	28476624	Alternatively, TMαBC could derepress rather than stimulate CLN6.
1		UNIPROT:P08174	activates	CLN6	UNIPROT:Q9NWW5	Protein	62b9a12c-bc4f-11e5-9b9d-001a4ae51247	PMC3427989	CR in the WT animals, however, caused profound suppression of multiple energy-modulatory factors including insulin-like growth factor 1 (Igf1), phospholipid transfer protein (Pltp), and neuronal ceroid lipofuscinosis 6 (Cln6), which were significantly downregulated following CR.
1		FPLX:ERK	activates	CLN6	UNIPROT:Q9NWW5	ProteinFamily	42fa3f94-bc32-11e5-8abe-001a4ae51246	PMC3597713	While it is interesting to speculate that the local increases in zinc levels in the CLN6 affected sheep may be responsible for the activation of the kinase pathways, further temporal studies are warranted to assess if metal accumulation leads to alterations of cellular phosphatases and sustained ERK1/2 activation in the CLN6 affected brain.
1		UNIPROT:Q15629	inhibits	CLN6	UNIPROT:Q9NWW5	Protein	9359b4f8-5c20-11e7-b441-001a4ae51247	PMC5479446	In addition, it has been reported that TRAM1, a protein involved in translocation of nascent polypeptides during ER stress, is also upregulated during UPR causing the rapid degradation of CLN6 mutants[92].
1		UNIPROT:Q9NWW5	activates	CLN6	UNIPROT:Q9NWW5	Protein	c8780b9a-3905-11e8-8636-001a4a160175	28065762	Notably, overexpression of CLN6 also increased LysoTracker intensity in control cells (Fig. 2B, C), implicating CLN6 in the regulation of vesicle pH or lysosomal biogenesis.