forked from pharmacome/conib
-
Notifications
You must be signed in to change notification settings - Fork 0
/
Copy pathdoyle2011.bel
1248 lines (1133 loc) · 61.3 KB
/
doyle2011.bel
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
699
700
701
702
703
704
705
706
707
708
709
710
711
712
713
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
749
750
751
752
753
754
755
756
757
758
759
760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
868
869
870
871
872
873
874
875
876
877
878
879
880
881
882
883
884
885
886
887
888
889
890
891
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
921
922
923
924
925
926
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
952
953
954
955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
972
973
974
975
976
977
978
979
980
981
982
983
984
985
986
987
988
989
990
991
992
993
994
995
996
997
998
999
1000
#######################
# Document Properties #
#######################
SET DOCUMENT Copyright = "Copyright © 2019 Fraunhofer Institute SCAI, All rights reserved."
SET DOCUMENT Licenses = "CC BY 4.0"
SET DOCUMENT ContactInfo = "[email protected]"
SET DOCUMENT Name = "Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders"
SET DOCUMENT Version = "1.0.0"
SET DOCUMENT Authors = "Trusha Adeshara"
SET DOCUMENT Description = "ER stress response plays a role in neurodegenerative disorders. This review summarizes the molecular events occurring during ER stress and the unfolded protein response"
##############
# Namespaces #
##############
# Namespaces hosted on https://github.com/pharmacome/terminology
# --------------------------------------------------------------
DEFINE NAMESPACE CHEBI AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/chebi-names.belns"
# DEFINE NAMESPACE DRUGBANK AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/drugbank-names.belns"
DEFINE NAMESPACE DOID AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c0c576e3d3ab9b25a3982251a4ee2fd7c49e1679/external/doid-names.belns"
# DEFINE NAMESPACE ECCODE AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/ec-code.belns"
# DEFINE NAMESPACE FB AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/fb-names.belns"
DEFINE NAMESPACE CONSO AS URL "https://raw.githubusercontent.com/pharmacome/conso/4aa36980578c7d2cff07371abf768f15db89cd11/export/conso-names.belns"
DEFINE NAMESPACE HGNC AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/hgnc-names.belns"
DEFINE NAMESPACE HGNCGENEFAMILY AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/hgnc.genefamily-names.belns"
DEFINE NAMESPACE HP AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/hp-names.belns"
DEFINE NAMESPACE GO AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/go-names.belns"
# DEFINE NAMESPACE INTERPRO AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/interpro-names.belns"
DEFINE NAMESPACE MESH AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/mesh-names.belns"
DEFINE NAMESPACE MGI AS URL "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/mgi-names.belns"
# DEFINE NAMESPACE MIRBASE AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/mirbase-names.belns"
# DEFINE NAMESPACE NCBIGENE AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/ncbigene.belns"
DEFINE NAMESPACE PFAM AS URL "https://raw.githubusercontent.com/pharmacome/terminology/c328ad964c08967a0417a887510b97b965a62fa5/external/pfam-names.belns"
# DEFINE NAMESPACE RGD AS URL "https://raw.githubusercontent.com/pharmacome/terminology/efc856fb009a39e4d284269a6801f79ed3d3cf56/external/rgd-names.belns"
# Namespaces hosted on https://github.com/sorgerlab/famplex
# ---------------------------------------------------------
DEFINE NAMESPACE FPLX AS URL "https://raw.githubusercontent.com/sorgerlab/famplex/d9ec0526c20795146a9a6aef17496efe1a36cac6/export/famplex.belns"
# Namespaces defined with regular expressions
# -------------------------------------------
# DEFINE NAMESPACE DBSNP AS PATTERN "rs[0-9]+"
# DEFINE NAMESPACE TAXONOMY AS PATTERN "^\d+$"
# DEFINE NAMESPACE UNIPROT AS PATTERN "^([A-N,R-Z][0-9]([A-Z][A-Z, 0-9][A-Z, 0-9][0-9]){1,2})|([O,P,Q][0-9][A-Z, 0-9][A-Z, 0-9][A-Z, 0-9][0-9])(\.\d+)?$"
# DEFINE NAMESPACE PUBCHEM AS PATTERN "^\d+$"
###############
# Annotations #
###############
# Annotations defined with regular expressions
# --------------------------------------------
DEFINE ANNOTATION Species AS PATTERN "^\d+$"
# Annotations hosted on https://arty.scai.fraunhofer.de/artifactory/bel/annotation
# --------------------------------------------------------------------------------
DEFINE ANNOTATION Anatomy AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/anatomy/anatomy-20170511.belanno"
# DEFINE ANNOTATION CellLine AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-line/cell-line-20170511.belanno"
DEFINE ANNOTATION CellStructure AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-structure/cell-structure-20170511.belanno"
DEFINE ANNOTATION Cell AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell/cell-20170511.belanno"
DEFINE ANNOTATION Confidence AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/confidence/confidence-1.0.0.belanno"
DEFINE ANNOTATION Disease AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/disease/disease-20170511.belanno"
# DEFINE ANNOTATION Gender AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/gender/gender-1.0.0.belanno"
DEFINE ANNOTATION MeSHAnatomy AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-anatomy/mesh-anatomy-20170511.belanno"
# DEFINE ANNOTATION MeSHDisease AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-diseases/mesh-diseases-20170511.belanno"
# DEFINE ANNOTATION Subgraph AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/neurommsig/neurommsig-1.0.3.belanno"
# DEFINE ANNOTATION TextLocation AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/text-location/text-location-1.0.1.belanno"
##############
# Statements #
##############
SET Citation = {"PubMed", "21722302"}
SET Evidence = "They include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and prion diseases [5]. Emerging evidence suggests that ER stress may play a pivotal role in the development or pathology of many neurodegenerative diseases."
SET Confidence = "High"
# they= neurodegenerative diseases
path(MESH:"Alzheimer Disease") -- path(CONSO:Neurodegeneration)
path(MESH:"Parkinson Disease") -- path(CONSO:Neurodegeneration)
path(MESH:"Amyotrophic Lateral Sclerosis") -- path(CONSO:Neurodegeneration)
path(MESH:"Prion Diseases") -- path(CONSO:Neurodegeneration)
bp(MESH:"Endoplasmic Reticulum Stress") -> path(CONSO:Neurodegeneration)
UNSET Confidence
SET Evidence = "Physiological or pathological processes that disturb protein folding in the ER cause ER stress. The cells initial and rapid response to ER stress is the activation of a set of pro-survival signalling pathways termed the UPR. Activation of the UPR causes a shutdown of global protein synthesis and activates mechanisms that allow the cell to deal with the accumulation of unfolded proteins. For example, it enhances the protein folding capacity by increasing the expression of ER chaperones and it up-regulates the degradation of misfolded proteins."
#UPR= unfolded protein response
SET Confidence = "High"
p(MESH:Proteins , pmod(CONSO:misfolded)) -- bp(MESH:"Endoplasmic Reticulum Stress")
bp(MESH:"Endoplasmic Reticulum Stress") -> bp(MESH:"Unfolded Protein Response")
bp(MESH:"Unfolded Protein Response") -| bp(GO:translation)
bp(MESH:"Unfolded Protein Response") -| bp(GO:"mRNA transcription")
bp(MESH:"Unfolded Protein Response") -> p(MESH:"Molecular Chaperones")
p(MESH:"Molecular Chaperones") -> bp(GO:"protein folding")
bp(MESH:"Unfolded Protein Response") -> deg(p(MESH:Proteins , pmod(CONSO:misfolded)))
UNSET Confidence
SET Evidence = "In mammals, the three major ER stress sensors are IRE1 (inositol requiring 1; ERN1, endoplasmic reticulum-to-nucleus signalling 1), PERK [double-stranded RNA-activated protein kinase (PKR)-like ER kinase; PEK, pancreatic eukaryotic initiation factor 2alpha kinase; EIF2AK3] and ATF6 (activating transcription factor 6)[6]."
#EIF2AK3 : PERK
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:ERN1)
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:EIF2AK3)
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:ATF6)
UNSET Confidence
SET Evidence = "The ER-luminal
domain of PERK, IRE1 and ATF6 interacts with the ER chaperone
glucose-regulated protein 78 (GRP78); however, upon accumulation
of unfolded proteins, GRP78 dissociates from these molecules,
leading to their activation [7]. Activation of PERK, IRE1 and
ATF6 initiates a network of intracellular signalling pathways during
the UPR (Fig. 1)"
SET Confidence = "High"
complex(p(HGNC:ERN1),p(HGNC:HSPA5)) -| act(p(HGNC:ERN1))
complex(p(HGNC:EIF2AK3),p(HGNC:HSPA5)) -| act(p(HGNC:EIF2AK3))
complex(p(HGNC:ATF6),p(HGNC:HSPA5)) -| act(p(HGNC:ATF6))
p(MESH:Proteins , pmod(CONSO:misfolded)) -> act(p(HGNC:ERN1))
p(MESH:Proteins , pmod(CONSO:misfolded)) -> act(p(HGNC:EIF2AK3))
p(MESH:Proteins , pmod(CONSO:misfolded)) -> act(p(HGNC:ATF6))
act(p(HGNC:ERN1)) -- bp(MESH:"Unfolded Protein Response")
act(p(HGNC:EIF2AK3)) -- bp(MESH:"Unfolded Protein Response")
act(p(HGNC:ATF6)) -- bp(MESH:"Unfolded Protein Response")
UNSET Confidence
SET Evidence = "The cytoplasmic domain
of IRE1 contains a serine/threonine kinase domain and a C-terminal
endoribonuclease domain [9]. ER stress leads to dissociation
of GRP78 from IRE1, resulting in autophosphorylation of IRE1alpha
and activation of its RNAse activity [9]."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:ERN1,pmod(Ph))
p(HGNC:ERN1,pmod(Ph)) -> act(p(HGNC:ERN1),ma(MESH:Ribonucleases))
UNSET Confidence
SET Evidence = "In addition, activated IRE1 can bind to tumour necrosis
factor (TNF)-receptor-associated factor 2 (TRAF2), an adaptor
protein that promotes activation of JUN N-terminal kinase (JNK)
through apoptosis signal-regulating kinase 1 (ASK1) [10]. JNK
activation results in enhanced autophagy [11]. This might allow
cells to adapt to stress by initiating autophagy."
#MAP3K5 - ASK1
SET Confidence = "High"
complex(p(HGNC:ERN1),p(HGNC:TRAF2)) -> p(HGNC:MAP3K5)
p(HGNC:MAP3K5) -> bp(GO:"JNK cascade")
bp(GO:"JNK cascade") -> bp(GO:autophagy)
UNSET Confidence
SET Evidence = "The pro-apoptotic B-cell lymphoma 2
(BCL-2) family members BCL-2–associated X protein (BAX) and
BCL-2 antagonist/killer (BAK) augment both the kinase and
endoribonuclease activities of IRE1. BAX and BAK form a protein
complex with the cytosolic domain of IRE1, which requires their
conserved BH1 and BH3 domains [12]."
SET Confidence = "High"
complex(GO:"BCL-2 complex") hasMembers list(p(HGNC:BAX),p(HGNC:BAK1))
p(HGNC:BAX) -> act(p(HGNC:ERN1), ma(kin))
p(HGNC:BAK1) -> act(p(HGNC:ERN1), ma(kin))
p(HGNC:BAX) -> act(p(HGNC:ERN1), ma(MESH:Endoribonucleases))
p(HGNC:BAK1) -> act(p(HGNC:ERN1), ma(MESH:Endoribonucleases))
UNSET Confidence
SET Evidence = "ASK1-interacting protein 1 (AIP1)
was recently shown to specifically regulate and enhance IRE1
signalling. [12]."
SET Confidence = "High"
p(HGNC:DAB2IP) -> act(p(HGNC:ERN1))
UNSET Confidence
SET Evidence = "We have recently shown
that the stress-inducible form of HSP70 (HSP72) can interact with
IRE1 and increase XBP1 mRNA splicing, thus modulating the
expression of XBP1’s target genes causing attenuated apoptosis
under ER stress conditions [13]. It is likely that additional proteins
can interact with IRE1 to alter its activity."
SET Confidence = "High"
composite(p(MESH:"HSP72 Heat-Shock Proteins"),p(HGNC:ERN1)) -> p(HGNC:XBP1)
p(HGNC:XBP1) -| bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "PERK-mediated phosphorylation
of the alpha subunit of eukaryotic translation initiation factor 2 alpha
(eIF2alpha) at Ser51 leads to translational attenuation [14]. Although
phosphorylation of eIF2alpha inhibits general translation initiation, it
paradoxically increases translation of activating transcription factor
4 (ATF4) [15] through a cap-independent process (Fig. 1)."
SET Confidence = "High"
p(HGNC:EIF2AK3) -> p(HGNC:EIF2A, pmod(Ph,S,51))
p(HGNC:EIF2A, pmod(Ph,S,51)) -| bp(GO:translation)
p(HGNC:EIF2A, pmod(Ph,S,51)) -> bp(GO:"cap-independent translational initiation")
bp(GO:"cap-independent translational initiation") -> p(HGNC:ATF4)
p(HGNC:EIF2A, pmod(Ph,S,51)) -> p(HGNC:ATF4)
UNSET Confidence
SET Evidence = "NRF2 is retained in the cytoplasm
through its association with the microtubule-associated protein
KEAP1 (Kelch-like Ech-associated protein 1) [16]. Upon ER stress,
PERK-mediated phosphorylation of NRF2 promotes its dissociation
from KEAP1, leading to the nuclear accumulation of NRF2
[16]. NRF2 binds to the antioxidant response element to activate
transcription of genes encoding detoxifying enzymes such as A1
and A2 subunits of glutathione S-transferase, NAD(P)H:quinone
oxidoreductase, gamma-glutamylcysteine synthetase, heme oxygenase-
1 and UDP-glucoronosyl transferase [16]."
#NFE2L2 - nuclear factor (erythroid-derived 2)/ NRF2
SET Confidence = "High"
p(HGNC:EIF2AK3) -| complex(p(HGNC:NFE2L2),p(HGNC:KEAP1))
p(HGNC:EIF2AK3) -> p(HGNC:NFE2L2, pmod(Ph),loc(MESH:"Cell Nucleus"))
p(HGNC:NFE2L2, pmod(Ph)) -> r(HGNCGENEFAMILY:"Soluble glutathione S-transferases")
p(HGNC:NFE2L2, pmod(Ph)) -> r(HGNCGENEFAMILY:"NADH:ubiquinone oxidoreductase core subunits")
p(HGNC:NFE2L2, pmod(Ph)) -> r(MESH:"Heme Oxygenase-1")
p(HGNC:NFE2L2, pmod(Ph)) -> r(MESH:"Glucuronosyltransferase")
p(HGNC:NFE2L2, pmod(Ph)) -> r(MESH:"Glutamate-Cysteine Ligase")
UNSET Confidence
SET Evidence = "In response to ER3
stress, GRP78 dissociation permits trafficking of ATF6 to the Golgi
complex, where ATF6 is sequentially cleaved by two proteases
[17]."
#HSPA5 : GRP78
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -| complex(p(HGNC:HSPA5),p(HGNC:ATF6))
bp(MESH:"Endoplasmic Reticulum Stress") -> tloc(p(HGNC:ATF6), fromLoc(GO:"endoplasmic reticulum membrane"), toLoc(GO:"Golgi apparatus"))
UNSET Confidence
SET Evidence = "ATF6 is responsible for
transcriptional induction of a cohort of ER proteins which includes
chaperones, folding enzymes and ER-associated degradation
(ERAD) components [18]. A number of other bZIP transcription
factors that localize to the ER have been identified including
OASIS, CREBH, LUMAN/CREB3, CREB4 and BBF2H7 [12]."
SET Confidence = "High"
p(HGNC:ATF6) -> a(MESH:"Molecular Chaperones")
p(HGNC:ATF6) -> bp(GO:"ERAD pathway")
UNSET Confidence
SET Evidence = "OASIS has been shown to be
involved in bone formation [19] and BBF2H7 targets Sec23a,
which governs protein transport from the ER to the Golgi."
SET Confidence = "High"
p(HGNC:CREB3L1) -> bp(MESH:"Bone Development")
p(HGNC:CREB3L2) reg p(HGNC:SEC23A)
p(HGNC:SEC23A) -> tloc(a(MESH:Proteins),fromLoc(GO:"endoplasmic reticulum"),toLoc(GO:"Golgi apparatus"))
UNSET Confidence
SET Evidence = "The most salient feature of the UPR is to increase the transactivation
function of an array of bZIP transcription factors such as
ATF6, ATF4, ATF3, NRF2 and XBP1. Once activated, these transcription
factors co-ordinate transcriptional induction of ER chaperones
and genes involved in ERAD, to enhance the protein folding
capacity of the cell and to decrease the unfolded protein load
of the ER, respectively [6]."
SET Confidence = "High"
bp(MESH:"Unfolded Protein Response") -> act(p(HGNC:ATF6))
bp(MESH:"Unfolded Protein Response") -> act(p(HGNC:ATF4))
bp(MESH:"Unfolded Protein Response") -> act(p(HGNC:ATF3))
bp(MESH:"Unfolded Protein Response") -> act(p(HGNC:NFE2L2))
bp(MESH:"Unfolded Protein Response") -> act(p(HGNC:XBP1))
p(HGNC:XBP1) -> a(MESH:"Molecular Chaperones")
p(HGNC:NFE2L2) -> a(MESH:"Molecular Chaperones")
p(HGNC:ATF3) -> a(MESH:"Molecular Chaperones")
p(HGNC:ATF4) -> a(MESH:"Molecular Chaperones")
p(HGNC:ATF6) -> a(MESH:"Molecular Chaperones")
a(MESH:"Molecular Chaperones") -- bp(GO:"ERAD pathway")
UNSET Confidence
SET Evidence = "Overall, it is thought that the apoptotic signals generated from
excessive activation of the UPR converge on the mitochondria
resulting in opening of the permeability transmembrane pore
(PTP) and loss of mitochondrial membrane potential (delta psi m) with
consequent release of pro-apoptotic factors, including
cytochrome c (Fig. 2)."
SET Confidence = "High"
bp(MESH:"Unfolded Protein Response") -> bp(GO:"apoptotic signaling pathway")
bp(GO:"apoptotic signaling pathway") -| complex(GO:"mitochondrial permeability transition pore complex")
complex(GO:"mitochondrial permeability transition pore complex") => bp(GO:"regulation of mitochondrial membrane potential")
bp(GO:"negative regulation of mitochondrial membrane potential") -> bp(GO:"release of cytochrome c from mitochondria")
UNSET Confidence
SET Evidence = "In conjunction with apoptotic protease activating
factor 1 (Apaf-1), pro-caspase-9 and cytochrome c form
the apoptosome [22, 23]. The apoptosome is a complex consisting
of adaptor proteins, which mediate the activation of initiator
caspases at the onset of apoptosis. Specifically it processes procaspase-
9 to its active form, which then activates downstream
effector caspases including caspase-3, -7 and -6 [24], leading to
apoptosis."
SET Confidence = "High"
composite(p(HGNC:APAF1),p(HGNC:CASP9),p(HGNC:CYC1)) -> a(MESH:Apoptosomes)
p(HGNC:CASP9) -> p(HGNC:CASP3)
p(HGNC:CASP9) -> p(HGNC:CASP7)
p(HGNC:CASP9) -> p(HGNC:CASP6)
composite(p(HGNC:CASP6),p(HGNC:CASP7),p(HGNC:CASP3)) -> bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "Caspase-4
has high homology to caspase-12 and its expression and cleavage
is increased during ER stress [2]."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:CASP4)
UNSET Confidence
SET Evidence = "Caspase-2 is cleaved in
response to excessive ER stress. Inhibition of caspase-2 confers
resistance to ER stress–induced apoptosis [28]."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:CASP2)
p(HGNC:CASP2) -> bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "Experimental evidence supports a role for
the BCL-2 family in ER stress–induced apoptosis. Overexpression
of BCL-2 can protect cells from ER stress–induced cell death [29].
Also, many of the BCL-2 family members associate with the ER
where they function to regulate Ca2+ homeostasis."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -- p(HGNC:BCL2)
p(HGNC:BCL2) -| bp(MESH:Apoptosis)
p(HGNC:BCL2) reg bp(GO:"calcium ion homeostasis")
UNSET Confidence
SET Evidence = "Pro-apoptotic members BAX and BAK cause
mitochondrial outer membrane permeabilization (MOMP) and formation
of the PTP, in a process which ultimately leads to release
of pro-apoptotic molecules such as second mitochondria-derived
activator of caspases and cytochrome c. Pro-apoptotic family
members sequester anti-apoptotic members such as BCL-2,
thereby tipping the balance towards death"
SET Confidence = "High"
p(HGNC:BAX) -- bp(MESH:Apoptosis)
p(HGNC:BAK1) -- bp(MESH:Apoptosis)
p(HGNC:BAX) -> bp(GO:"mitochondrial outer membrane permeabilization")
p(HGNC:BAK1) -> bp(GO:"mitochondrial outer membrane permeabilization")
p(HGNC:BAX) -> complex(GO:"mitochondrial permeability transition pore complex")
p(HGNC:BAK1) -> complex(GO:"mitochondrial permeability transition pore complex")
complex(GO:"mitochondrial permeability transition pore complex") -> bp(GO:"release of cytochrome c from mitochondria")
complex(GO:"mitochondrial permeability transition pore complex") -> p(MESH:Caspases)
p(HGNC:BCL2) -| bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "ER stress induces expression of the BH3-only proteins BIM,
PUMA and NOXA and can also down-regulate expression of BCL-
2 and cause cell death. Overexpression of PUMA induced apoptosis,
whereas PUMA-/- cells were resistant to ER stress–induced
apoptosis [31]."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -> complex(GO:"BIM-BCL-2 complex")
bp(MESH:"Endoplasmic Reticulum Stress") -> complex(GO:"PUMA-BCL-2 complex")
bp(MESH:"Endoplasmic Reticulum Stress") -> complex(GO:"NOXA-BCL-2 complex")
bp(MESH:"Endoplasmic Reticulum Stress") -| p(HGNC:BCL2)
complex(GO:"PUMA-BCL-2 complex") -> bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "CHOP, also known as growth arrest and DNA damage-inducible
gene 153 (GADD153), is a member of the C/EBP family that heterodimerizes
with other members of the C/EBP transcription factor
family. This 29 kD factor is expressed at low levels in
unstressed cells and is strongly induced in response to ER stress
[33]. It can be induced by all three arms of the UPR. It has been
shown that mouse embryonic fibroblasts derived from CHOP-/-
animals exhibited significantly less cell death when challenged
with ER stress–inducing agents compared to wild type [33]."
#DDIT3 - CHOP
SET Confidence = "High"
p(HGNC:DDIT3) -> bp(MESH:"DNA Damage")
p(HGNC:DDIT3) -- complex(GO:"CHOP-C/EBP complex")
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:DDIT3)
bp(MESH:"Unfolded Protein Response") -> p(HGNC:DDIT3)
SET Species = "10090"
SET Cell = "embryonic fibroblast"
p(HGNC:DDIT3) -> bp(MESH:"Cell Death")
UNSET Cell
UNSET Species
UNSET Confidence
SET Evidence = "CHOP’s pro-apoptotic effects are linked to down-regulation of
BCL-2 and enhanced production of reactive oxygen species (ROS)
[34]. Caspase-11 has been reported to act downstream of
CHOP to induce cell death by activating death effector caspases-1 and -3 [35]."
SET Confidence = "High"
p(HGNC:DDIT3) -| p(HGNC:BCL2)
p(HGNC:DDIT3) -> a(MESH:"Reactive Oxygen Species")
p(HGNC:DDIT3) -> p(MGI:Casp4)
p(MGI:Casp4) -> p(HGNC:CASP1)
p(MGI:Casp4) -> p(HGNC:CASP3)
act(p(HGNC:CASP1)) -> bp(MESH:"Cell Death")
act(p(HGNC:CASP3)) -> bp(MESH:"Cell Death")
UNSET Confidence
SET Evidence = "CHOP can also bind to the promoter region of proapoptotic
BIM, increasing its expression as well as transcriptionally
down-regulating BCL-2 and in this way it induces cell death."
SET Confidence = "High"
p(HGNC:DDIT3) -> complex(GO:"BIM-BCL-2 complex")
p(HGNC:DDIT3) -| r(HGNC:BCL2)
complex(GO:"CHOP-C/EBP complex") -> bp(MESH:"Cell Death")
UNSET Confidence
SET Evidence = "Accumulating evidence indicates that autophagy may
confer neuroprotection by enhancing clearance of soluble and
aggregated misfolded proteins and conversely, deregulation of
autophagy may lead to neurodegeneration [37]."
SET Confidence = "High"
bp(GO:autophagy) -> bp(MESH:Neuroprotection)
bp(GO:autophagy) -| p(MESH:Proteins , pmod(CONSO:misfolded))
bp(GO:autophagy) -- path(MESH:"Neurodegenerative Diseases")
UNSET Confidence
SET Evidence = "misfolded or
unassembled proteins are retained in the ER and subsequently
degraded by ERAD. In the ERAD pathway, ER-resident chaperones
recognize the misfolded proteins and ER reductases remove disulfide
bonds in these proteins to facilitate retrograde transport to the
cytosol where they are degraded by the proteasome [38]."
SET Confidence = "High"
SET CellStructure = "Endoplasmic Reticulum"
bp(GO:"ERAD pathway") -> deg(p(MESH:Proteins , pmod(CONSO:misfolded)))
p(MESH:Oxidoreductases) -> tloc(p(MESH:Proteins , pmod(CONSO:misfolded)),fromLoc(GO:"endoplasmic reticulum"),toLoc(GO:cytoplasm))
UNSET CellStructure
SET CellStructure = "Cytoplasm"
p(HGNCGENEFAMILY:Proteasome) -| deg(p(MESH:Proteins,pmod(CONSO:misfolded)))
UNSET CellStructure
UNSET Confidence
SET Evidence = "To
remove the aggregates of misfolded proteins that cannot be
degraded by the ERAD, the UPR activates autophagy [11]. During
ER stress–induced autophagy, portions of the ER and protein
aggregates are engulfed in double-membrane structures called
autophagosomes and delivered to lysosomes for degradation
[39]. The initiation of autophagy requires activation of the
ATG1/ULK induction complex [40]. This complex is essential for
the formation of a small double membrane structure known as a
phagophore, which will eventually mature into a double-membraned
vacuole termed an autophagosome [41]."
SET Confidence = "High"
bp(MESH:"Unfolded Protein Response") -> bp(GO:autophagy)
composite(a(MESH:Autophagosomes),a(MESH:Lysosomes)) -> deg(a(MESH:Autophagosomes))
complex(GO:"Atg1/ULK1 kinase complex") -> bp(GO:autophagy)
complex(GO:"Atg1/ULK1 kinase complex") -> a(GO:phagophore)
a(GO:phagophore) -> a(MESH:Autophagosomes)
UNSET Confidence
SET Evidence = "Mammalian target of rapamycin (mTOR) is a key kinase in the
regulation of autophagy and activated mTOR inhibits autophagy.
mTOR exists in two different complex forms, mTOR complex I
(mTORC1) and mTOR complex II [42]."
SET Confidence = "High"
p(HGNC:MTOR) reg bp(GO:autophagy)
act(p(HGNC:MTOR)) -| bp(GO:autophagy)
p(HGNC:MTOR) hasComponents list(p(HGNCGENEFAMILY:"MTOR complex 1"),p(HGNCGENEFAMILY:"MTOR complex 2"))
UNSET Confidence
SET Evidence = "AMP-activated protein
kinase (AMPK) negatively regulates mTOR via the tuberous sclerosis
complex (TSC). AMPK is activated in response to many
stresses such as hypoxia, starvation, heat shock, ischaemia and
ER stress [43]. During ER stress, Ca2+ flux from the ER lumen
to the cytosol can lead to the activation of Ca2+/calmodulindependent
protein kinase kinase-beta (CaMKK-beta) [44]. CaMKK-beta
activates AMPK, in turn inhibiting mTOR and activating the
ATG/ULK induction complex. The inhibition of mTOR during ER
stress via AMPK is an important event during ER stress for the
induction of autophagy [45]."
SET Confidence = "High"
p(HGNC:PRKAA1) neg p(HGNC:MTOR)
p(HGNC:PRKAA1) reg p(HGNCGENEFAMILY:"TSC complex")
p(HGNCGENEFAMILY:"TSC complex") reg p(HGNC:MTOR)
path(MESH:Hypoxia) -> act(p(HGNC:PRKAA1))
path(MESH:Starvation) -> act(p(HGNC:PRKAA1))
bp(MESH:"Heat-Shock Response") -> act(p(HGNC:PRKAA1))
bp(MESH:"Endoplasmic Reticulum Stress") -> act(p(HGNC:PRKAA1))
path(MESH:Ischemia) -> act(p(HGNC:PRKAA1))
bp(MESH:"Endoplasmic Reticulum Stress") -> tloc(a(CHEBI:"calcium cation"),fromLoc(GO:"endoplasmic reticulum"),toLoc(GO:cytoplasm))
a(CHEBI:"calcium cation",loc(GO:cytoplasm)) -> act(p(HGNC:CAMK2B))
p(HGNC:CAMK2B) -> act(p(HGNC:PRKAA1))
p(HGNC:PRKAA1) -| p(HGNC:MTOR)
p(HGNC:CAMK2B) -> act(complex(GO:"Atg1/ULK1 kinase complex"))
p(HGNC:MTOR) -| bp(GO:autophagy)
UNSET Confidence
SET Evidence = "Different conditions that induce ER stress lead to induction of
autophagy [39]. Both the PERK/eIF2alpha and IRE1 arms of the UPR
have been implicated in the regulation of autophagy [46, 47].
Treatment of cells with tunicamycin, thapsigargin or proteasome
inhibitors induces autophagy in an IRE1-dependent manner [47]."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -> bp(GO:autophagy)
p(HGNC:EIF2AK3) reg bp(GO:autophagy)
p(HGNC:ERN1) reg bp(GO:autophagy)
a(CHEBI:tunicamycin) -> bp(GO:autophagy)
a(CHEBI:thapsigargin) -> bp(GO:autophagy)
a(MESH:"Proteasome Inhibitors") -> bp(GO:autophagy)
UNSET Confidence
SET Evidence = "The pro-autophagic actions of IRE1 seem to rely on the ability of
IRE1 to activate JNK. JNK has been shown to regulate autophagy
through BCL-2 phosphorylation, which disrupts its interaction
with Beclin-1 [48]."
SET Confidence = "High"
p(HGNC:ERN1) -> bp(GO:"JNK cascade")
bp(GO:"JNK cascade") reg bp(GO:autophagy)
bp(GO:"JNK cascade") -> p(HGNC:BCL2,pmod(Ph))
p(HGNC:BCL2,pmod(Ph)) -| composite(a(MESH:"Beclin-1"),p(HGNC:BCL2))
UNSET Confidence
SET Evidence = "Intriguingly, it has been recently shown that
XBP1 ablation increases autophagy and protects cells from the
toxicity induced by aggregates of the mutant form of enzyme
superoxide dismutase 1 (mSOD1) in a model of ALS [49]."
SET Confidence = "High"
SET Disease = "amyotrophic lateral sclerosis"
p(HGNC:XBP1) -| bp(GO:autophagy)
p(HGNC:XBP1) -> p(HGNC:SOD1,pmod(MESH:"Mutant Proteins"))
p(HGNC:SOD1,pmod(MESH:"Mutant Proteins")) -> bp(CONSO:"protein aggregation")
bp(CONSO:"protein aggregation") -> bp(MESH:"Cell Death")
UNSET Disease
UNSET Confidence
SET Evidence = "It has been shown that PERK signalling is also required for
autophagy following expression of the Huntington’s disease-associated
expanded polyglutamine repeats, which is a result of expansion
of a CAG trinucleotide repeat and extension of a polyglutamine
tract at the N-terminus of the encoded, ubiquitously
expressed protein called huntingtin [50]. PERK-eIF2alpha–dependent
ATG12 up-regulation is required for induction of autophagy in
response to polyglutamine protein accumulation [51]."
SET Confidence = "High"
SET Disease = "Huntington's disease"
p(HGNC:HTT,pmod(MESH:polyglutamine)) -> p(HGNC:EIF2AK3)
p(HGNC:EIF2AK3) -> bp(GO:autophagy)
p(HGNC:EIF2AK3) -> p(HGNC:ATG12)
composite(p(HGNC:ATG12),p(HGNC:HTT,pmod(MESH:polyglutamine))) -> bp(GO:autophagy)
UNSET Disease
UNSET Confidence
SET Evidence = "PERKdependent
transcription factors ATF4 and CHOP have been shown
to induce transcriptional activation of MAP1LC3B and ATG5 during
hypoxia [52]. Further, eIF2alpha-dependent up-regulation of the
transcription factors p8, ATF4, CHOP and TRB3 is required for
induction of autophagy [53]."
SET Confidence = "High"
SET MeSHDisease = "Hypoxia"
p(HGNC:EIF2AK3) -> p(HGNC:DDIT3)
p(HGNC:EIF2AK3) -> p(HGNC:ATF4)
p(HGNC:ATF4) -> p(HGNC:MAP1LC3B)
p(HGNC:ATF4) -> p(HGNC:ATG5)
p(HGNC:DDIT3) -> p(HGNC:MAP1LC3B)
p(HGNC:DDIT3) -> p(HGNC:ATG5)
p(HGNC:EIF2A) -> p(HGNC:NUPR1)
p(HGNC:EIF2A) -> p(HGNC:ATF4)
p(HGNC:EIF2A) -> p(HGNC:DDIT3)
p(HGNC:EIF2A) -> p(HGNC:TRIB3)
p(HGNC:DDIT3) -> bp(GO:autophagy)
p(HGNC:NUPR1) -> bp(GO:autophagy)
p(HGNC:ATF4) -> bp(GO:autophagy)
p(HGNC:TRIB3) -> bp(GO:autophagy)
UNSET MeSHDisease
UNSET Confidence
SET Evidence = "Protein folding in vivo is an inefficient process and is aided by
molecular chaperones, which increase folding efficiency. In addition,
degradation systems such as ERAD, the endo-lysosomal
pathway, the proteasome and autophagy rapidly remove misfolded
proteins.[38]."
SET Confidence = "High"
p(MESH:"Molecular Chaperones") -> bp(GO:"protein folding")
bp(GO:"ERAD pathway") -> deg(p(MESH:Proteins , pmod(CONSO:misfolded)))
bp(GO:"lysosomal protein catabolic process") -> deg(p(MESH:Proteins , pmod(CONSO:misfolded)))
p(HGNCGENEFAMILY:Proteasome) -> deg(p(MESH:Proteins , pmod(CONSO:misfolded)))
bp(GO:autophagy) -> deg(p(MESH:Proteins,pmod(CONSO:misfolded)))
UNSET Confidence
SET Evidence = "Neurons are
heavily reliant on the removal of misfolded proteins to maintain
homeostasis [56] and accumulation of misfolded proteins is a
characteristic feature of many neurodegenerative diseases including
AD [57], PD [58], transmissible spongiform encephalopathy
[59] and also acute neurodegenerative disorders such as
traumatic brain injury [60] and cerebral ischaemia [61]."
SET Confidence = "High"
p(MESH:Proteins , pmod(CONSO:misfolded)) -> bp(CONSO:"protein aggregation")
SET Cell = "neuron"
bp(CONSO:"protein aggregation") -- path(MESH:"Neurodegenerative Diseases")
bp(CONSO:"protein aggregation") -- path(MESH:"Alzheimer Disease")
bp(CONSO:"protein aggregation") -- path(MESH:"Parkinson Disease")
bp(CONSO:"protein aggregation") -- path(MESH:"Amyloidosis, Cerebral, with Spongiform Encephalopathy")
bp(CONSO:"protein aggregation") -- path(MESH:"Brain Injuries, Traumatic")
bp(CONSO:"protein aggregation") -- path(MESH:"Brain Ischemia")
UNSET Cell
UNSET Confidence
SET Evidence = "Because
misfolded proteins trigger the UPR, this has prompted several
groups to investigate the involvement of ER stress in neurodegenerative
disorders."
SET Confidence = "High"
p(MESH:Proteins , pmod(CONSO:misfolded)) -> bp(MESH:"Unfolded Protein Response")
bp(MESH:"Endoplasmic Reticulum Stress") -- path(MESH:"Neurodegenerative Diseases")
UNSET Confidence
SET Disease = "Alzheimer's disease"
SET Evidence = "AD is characterized by the presence of senile plaques with a core
of extracellular beta-amyloid protein and intracellular neurofibrillary
tangles containing hyperphosphorylated tau [62]."
SET Confidence = "High"
path(MESH:"Alzheimer Disease") -- path(HP:"Senile plaques")
path(HP:"Senile plaques") -> a(CONSO:"amyloid-beta aggregates")
path(HP:"Senile plaques") -> a(MESH:"Neurofibrillary Tangles")
a(MESH:"Neurofibrillary Tangles") -> p(HGNC:MAPT,pmod(CONSO:hyperphosphorylation))
UNSET Confidence
SET Evidence = "These pathological
hallmarks are accompanied by ballooning of neurites and
neuronal loss. Beta-Amyloid is cleaved from its precursor protein,
amyloid precursor protein (APP), through the action of Gamma-secretase
(BACE) and gamma-secretase that results in the production of
beta-amyloid protein. Gamma-Secretase can produce beta-amyloid of different
lengths, most notably Abeta40 and Abeta42 [63]."
SET Confidence = "High"
path(MESH:Neurites) -- path(MESH:"Alzheimer Disease")
bp(GO:"neuron death") prognosticBiomarkerFor path(MESH:"Alzheimer Disease")
p(HGNC:APP) -> a(CHEBI:"amyloid-beta")
p(HGNC:BACE1) -> rxn(reactants(p(HGNC:APP)),products(a(CHEBI:"amyloid-beta")))
complex(FPLX:"Gamma_secretase") -> rxn(reactants(p(HGNC:APP)),products(a(CHEBI:"amyloid-beta")))
complex(FPLX:"Gamma_secretase") -> p(HGNC:APP, frag(672_713))
#frag(672_713) is Abeta42
complex(FPLX:"Gamma_secretase") -> p(HGNC:APP, frag(672_711))
#frag(672_711) is Abeta40
UNSET Confidence
SET Evidence = "The Abeta42 form of
the protein is the most amyloidogenic and is prevalent in senile
plaques. The extracellular deposition of senile plaques may precede
the development of neurofibrillary tangles, and has been the
subject of much investigative interest [64]."
SET Confidence = "High"
p(HGNC:APP, frag(672_713)) isA a(MESH:"Amyloidogenic Proteins")
p(HGNC:APP, frag(672_713)) -> path(HP:"Senile plaques")
SET CellStructure = "Extracellular Space"
path(HP:"Senile plaques") -> a(MESH:"Neurofibrillary Tangles")
UNSET CellStructure
UNSET Confidence
SET Evidence= "Although the evolution
of senile plaques is closely linked to the development of the neurodegeneration
and onset and progression of symptoms in AD,
there is arguably not a direct causal relationship between beta-amyloid
deposition and neurodegeneration.[65]."
SET Confidence = "High"
path(HP:"Senile plaques") -- path(MESH:"Neurodegenerative Diseases")
a(CONSO:"amyloid-beta aggregates") -- path(CONSO:Neurodegeneration)
UNSET Confidence
SET Evidence = "Neurofibrillary
tangles contain twisted pairs of helical filaments formed by the
aggregation of hyperphosphorylated tau [69]. Hyperphosphorylation
of tau impairs its ability to interact with cytoskeletal microfilaments,
resulting in disorganization of the cytoskeleton."
SET Confidence = "High"
a(MESH:"Neurofibrillary Tangles") -> p(HGNC:MAPT,pmod(CONSO:hyperphosphorylation))
p(HGNC:MAPT,pmod(CONSO:hyperphosphorylation)) -| bp(GO:"cytoskeleton organization")
UNSET Confidence
SET Evidence = "The presenilin protein is a component of the Gamma-secretase complex,
which is widely expressed in the ER and Golgi apparatus
[70]. Presenilin mutations are linked with the majority of early
onset forms of AD [69] with presenilin 1 (PS1) being more highly
expressed than PS2, and mutations in the genes coding for a presenilin
protein reduce the average age of onset of AD [71]."
SET Confidence = "High"
SET CellStructure = {"Endoplasmic Reticulum","Golgi Apparatus"}
complex(FPLX:"Gamma_secretase") hasComponent p(PFAM:Presenilin)
p(PFAM:Presenilin,var("?")) -- path(MESH:"Alzheimer Disease")
path(MESH:"Alzheimer Disease") -> p(HGNC:PSEN1)
p(PFAM:Presenilin,var("?")) -| path(MESH:"Age of Onset")
UNSET CellStructure
UNSET Confidence
SET Evidence = "Evidence also demonstrates that PS1 mutations render cells more
susceptible to apoptosis induced by a range of insults [72].
Presenilin is an integral membrane protein that is located primarily
in ER and has been shown to influence the activity of two of
the key ER stress sensors IRE1 and PERK (Fig. 3A). Presenilin
mutations reduced phosphorylation of PERK and eIF2alpha, resulting
in failure to attenuate protein synthesis causing protein accumulation
in the ER [73]."
#PSEN1 - PS1
SET Confidence = "High"
p(HGNC:PSEN1,var("?")) -> bp(MESH:Apoptosis)
p(PFAM:Presenilin) isA complex(GO:"ER membrane protein complex")
p(PFAM:Presenilin) -- p(HGNC:ERN1)
p(PFAM:Presenilin) -- p(HGNC:EIF2AK3)
p(PFAM:Presenilin) -| p(HGNC:EIF2AK3,pmod(Ph))
p(PFAM:Presenilin) -| p(HGNC:EIF2A,pmod(Ph))
SET CellStructure = "Endoplasmic Reticulum"
p(HGNC:EIF2AK3,pmod(Ph)) -> bp(CONSO:"protein aggregation")
p(HGNC:EIF2A,pmod(Ph)) -> bp(CONSO:"protein aggregation")
UNSET CellStructure
UNSET Confidence
SET Evidence = "Mutant PS1 is also known to bind, and inhibit
IRE1, thereby reducing, or delaying, the transcription of ER chaperones
such as GRP78 which has consistently been found to
be down-regulated in AD [73]."
SET Confidence = "High"
p(HGNC:PSEN1,var("?")) -| p(HGNC:ERN1)
p(HGNC:PSEN1,var("?")) -| r(HGNC:HSPA5)
path(MESH:"Alzheimer Disease") neg p(HGNC:HSPA5)
UNSET Confidence
SET Evidence = "In fact, the increased sensitivity
of neurons to ER stress is attributed to the decreased levels of
GRP78 mRNA. We have recently demonstrated that modulation of
IRE1 activity and the resultant effect on XBP1 splicing can regulate
cell fate [13]. Therefore, it is possible that mutant PS1, acting
on IRE1, can reduce or delay splicing of XBP1, thus switching signalling
to a pro-death response."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -| r(HGNC:HSPA5)
p(HGNC:ERN1) reg p(HGNC:XBP1)
p(HGNC:PSEN1,var("?")) -| r(HGNC:XBP1)
UNSET Confidence
SET Evidence = "XBP1 can bind to the promotors of at least
one key component of the Gamma-secretase complex, namely UBQLN1
that is a negative regulator of the Gamma-secretase complex. It has been
suggested that UBQLN1 may control APP trafficking and thus the
generation of Abeta. XBP1 can also bind to the promoter of genes
involved in APP trafficking and processing as well as genes
involved in AD pathogenesis, thereby implicating XBP1 in AD
(Fig. 3A) [75]."
SET Confidence = "High"
p(HGNC:XBP1) reg g(FPLX:"Gamma_secretase")
p(HGNC:UBQLN1) neg complex(FPLX:"Gamma_secretase")
p(HGNC:UBQLN1) reg p(HGNC:APP)
p(HGNC:UBQLN1) reg a(CHEBI:"amyloid-beta")
p(HGNC:XBP1) reg p(HGNC:APP)
p(HGNC:XBP1) -- path(MESH:"Alzheimer Disease")
UNSET Confidence
SET Evidence = "It is possible therefore that reduced expression of
XBP1 in AD influences the generation of Abeta and affects cell fate
decisions."
SET Confidence = "High"
p(HGNC:XBP1) neg path(MESH:"Alzheimer Disease")
p(HGNC:XBP1) -- a(CHEBI:"amyloid-beta")
UNSET Confidence
SET Evidence = "Ca2+ homeostasis is important for proper functioning of ER
chaperones and protein folding. Alterations in Ca2+ homeostasis
lead to reduced chaperone activity, protein misfolding and initiation
of the UPR. Abeta peptides have been shown to cause depletion
of ER Ca2+ stores by triggering release of Ca2+ into the cytoplasm."
SET Confidence = "High"
bp(GO:"calcium ion homeostasis") -> p(MESH:"Molecular Chaperones",loc(GO:"endoplasmic reticulum"))
bp(GO:"calcium ion homeostasis") -> act(p(MESH:"Molecular Chaperones",loc(GO:"endoplasmic reticulum")))
bp(GO:"calcium ion homeostasis") -> bp(GO:"protein folding")
bp(GO:"calcium ion homeostasis") -> bp(MESH:"Unfolded Protein Response")
a(CHEBI:"amyloid-beta") -| tloc(a(CHEBI:"calcium cation"),fromLoc(GO:"endoplasmic reticulum"),toLoc(GO:cytoplasm))
UNSET Confidence
SET Evidence = "In addition, PS1 mutations increase Abeta42 levels and have also been shown to impair ER Ca2+ homeostasis. Cells containing
human PS1 mutations exhibit increased Ca2+ release from intracellular
stores in response to stress in vitro [76]. Therefore, current
studies suggest that there is a perturbed UPR response in AD."
SET Confidence = "High"
p(HGNC:PSEN1,var("?")) -> p(HGNC:APP, frag(672_713))
SET CellStructure = "Endoplasmic Reticulum"
p(HGNC:PSEN1,var("?")) -| bp(GO:"calcium ion homeostasis")
UNSET CellStructure
p(HGNC:PSEN1,var("?")) -> tloc(a(CHEBI:"calcium cation"),fromLoc(GO:"endoplasmic reticulum"),toLoc(GO:cytoplasm))
path(MESH:"Alzheimer Disease") -| bp(MESH:"Unfolded Protein Response")
UNSET Confidence
SET Evidence = "Autophagosomes and precursor autophagosomes (autophagic
vacuoles) are abundant in swollen and dystrophic neurites from
human AD brains, suggesting that the later stages of autophagy or
the removal of autophagic vacuoles may be deregulated [77]."
SET Confidence = "High"
SET MeSHAnatomy = "Brain"
path(MESH:"Alzheimer Disease") -- a(GO:autophagosome)
path(MESH:"Alzheimer Disease") neg bp(GO:autophagy)
UNSET MeSHAnatomy
UNSET Confidence
UNSET Disease
SET Disease = "Parkinson's disease"
SET Evidence = "PD is characterized by motor symptoms such as dyskinesia, muscle
rigidity, postural instability and resting tremor. In addition,
olfactory sensory loss and gastrointestinal disturbance are common
in PD sufferers. Degeneration of the dopaminergic neurones
of the nigrostriatal pathway and the presence of alpha-synuclein containing
Lewy bodies and Lewy neurites are characteristic of the
disease [78]."
SET Confidence = "High"
path(HP:Dyskinesia) prognosticBiomarkerFor path(MESH:"Parkinson Disease")
path(MESH:"Muscle Rigidity") prognosticBiomarkerFor path(MESH:"Parkinson Disease")
path(HP:"Postural instability") prognosticBiomarkerFor path(MESH:"Parkinson Disease")
path(HP:"Resting tremor") prognosticBiomarkerFor path(MESH:"Parkinson Disease")
path(DOID:"olfactory nerve disease") prognosticBiomarkerFor path(MESH:"Parkinson Disease")
path(CONSO:"Gastrointestinal dysfunctions") prognosticBiomarkerFor path(MESH:"Parkinson Disease")
path(MESH:"Parkinson Disease") -| a(MESH:"Dopaminergic Neurons")
a(GO:"Lewy body") -> p(HGNC:SNCA)
a(GO:"Lewy neurite") biomarkerFor path(MESH:"Parkinson Disease")
a(GO:"Lewy body") biomarkerFor path(MESH:"Parkinson Disease")
UNSET Confidence
SET Evidence = "Within the Lewy plaques, diffuse deposits of misfolded
alpha-synuclein form the core in association with other proteins,
notably components of the ubiquitin–proteasome system
[3]."
SET Confidence = "High"
a(GO:"Lewy body") -> p(HGNC:SNCA,pmod(CONSO:misfolded))
UNSET Confidence
SET Evidence = "Genes associated with autosomal
dominant PD include alpha-synuclein, ubiquitin carboxyl-terminal
esterase L1 (UCHL1) and leucine-rich repeat kinase 2 (LRRK2);
autosomal recessive PD genes include Parkinson protein 2
(PARK2/Parkin); PTEN-induced kinase 1 (PARK6/PINK1); PD(autosomal recessive, early onset) 7 (PARK7/DJ-1) and PD (autosomal
recessive) 9; (PARK9/ATP13A2) [80]."
SET Confidence = "High"
path(DOID:"autosomal dominant Parkinson's disease 1") -- g(HGNC:SNCA)
path(DOID:"autosomal dominant Parkinson's disease 1") -- g(HGNC:UCHL1)
path(DOID:"autosomal dominant Parkinson's disease 1") -- g(HGNC:LRRK2)
path(DOID:"autosomal recessive Parkinson's disease 14") -- g(HGNC:PRKN)
path(DOID:"autosomal recessive Parkinson's disease 14") -- g(HGNC:PINK1)
path(DOID:"autosomal recessive Parkinson's disease 14") -- g(HGNC:PARK7)
path(DOID:"autosomal recessive Parkinson's disease 14") -- g(HGNC:ATP13A2)
UNSET Confidence
SET Evidence = "Alpha-Synuclein is expressed in synaptic vesicles and on cell membranes
in nervous tissue. Post-translational modification of
alpha-synuclein such as phosphorylation and nitrosylation can cause
misfolding and subsequent deposition of the protein [78]. There is a suggestion
that alpha-synuclein, although normally contained within
cells, may be released upon cell death [78]."
SET Confidence = "High"
SET Anatomy = "nervous system"
SET CellStructure = {"Synaptic Vesicles","Cell Membrane"}
p(HGNC:SNCA)
p(HGNC:SNCA,pmod(Ph)) -> p(HGNC:SNCA,pmod(CONSO:misfolded))
p(HGNC:SNCA,pmod(NO)) -> p(HGNC:SNCA,pmod(CONSO:misfolded))
p(HGNC:SNCA,pmod(CONSO:misfolded)) -> a(CONSO:"alpha-synuclein aggregates")
bp(MESH:"Cell Death") -> tloc(p(HGNC:SNCA),fromLoc(GO:"intracellular"), toLoc(GO:"extracellular space"))
UNSET CellStructure
UNSET Anatomy
UNSET Confidence
SET Evidence = "Missense mutations in the gene coding for
alpha-synuclein cause dominant familial PD. The A53T mutation is
associated with UPR activation as evidenced by increased expression
of CHOP and GRP78 and increased phosphorylation of eIF2alpha,
suggesting the UPR is active in these cells (Fig. 3B) [80].Inhibition of phosphorylation of eIF2alpha protected the A53T alpha-
synuclein-overexpressing cells from cell death, suggesting that the
activated UPR was shifting the balance towards apoptosis [80]."
SET Confidence = "High"
p(HGNC:SNCA,var("?")) -> path(DOID:"autosomal dominant Parkinson's disease 1")
p(HGNC:SNCA,var("p.Ala53Thr")) -> bp(MESH:"Unfolded Protein Response")
bp(MESH:"Unfolded Protein Response") -> p(HGNC:DDIT3)
bp(MESH:"Unfolded Protein Response") -> p(HGNC:HSPA5)
bp(MESH:"Unfolded Protein Response") -> p(HGNC:EIF2A, pmod(Ph))
composite(p(HGNC:EIF2A, pmod(Ph)),p(HGNC:SNCA,var("p.Ala53Thr"))) -> bp(MESH:"Cell Death")
bp(MESH:"Unfolded Protein Response") -> bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "LRRK2 mutations also cause dominant familial PD, and may
also account for a number of previously considered sporadic
cases of PD [81,82]. Mutations in LRRK2 cause impairment of
protein degradation pathways with ageing [82]. This can lead to
accumulation of alpha-synuclein and ubiquitinated proteins,
impairment of the autophagy-lysosomal pathway, accumulation
of oxidised proteins, an inflammatory response and increased
apoptosis [82]."
SET Confidence = "High"
p(HGNC:LRRK2,var("?")) -> path(DOID:"autosomal dominant Parkinson's disease 1")
p(HGNC:LRRK2,var("?")) -| bp(GO:"protein catabolic process")
p(HGNC:LRRK2,var("?")) -> a(CONSO:"alpha-synuclein aggregates")
p(HGNC:LRRK2,var("?")) -> a(MESH:"Ubiquitinated Proteins")
p(HGNC:LRRK2,var("?")) -| bp(GO:"lysosomal protein catabolic process")
p(HGNC:LRRK2,var("?")) -| bp(GO:"regulation of protein oxidation")
p(HGNC:LRRK2,var("?")) -> bp(GO:"inflammatory response")
p(HGNC:LRRK2,var("?")) -> bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "UCH-L1 mutations are linked to autosomal-dominant PD, however
the mechanism by which it caused the disease is unclear, with
conflicting evidence reported for its in vivo functions. Recent studies
reveal a role for UCH-L1 in chaperone-mediated autophagy
(CMA) and mutant UCH-L1 was shown to inhibit CMA-mediated
removal of alpha-synuclein [83]."
SET Confidence = "High"
p(HGNC:UCHL1,var("?")) -- path(DOID:"autosomal dominant Parkinson's disease 1")
p(HGNC:UCHL1) -- bp(GO:"chaperone-mediated autophagy")
p(HGNC:UCHL1,var("?")) -| bp(GO:"chaperone-mediated autophagy")
bp(GO:"chaperone-mediated autophagy") -> deg(a(CONSO:"alpha-synuclein aggregates"))
UNSET Confidence
SET Evidence = "Several genetic mutations have been linked to the recessive
form of PD including Parkin, an E3 ligase which forms part of the
cascade reaction which targets misfolded proteins for degradation
by the proteasome [84]. Mutations in Parkin result in loss of ubiquitin-
protein ligase activity [85, 86], which can result in the accumulation
of misfolded proteins within cells and may underpin the
development of PD in people with this genetic mutation [85, 86]."
#PRKN - Parkin
SET Confidence = "High"
g(HGNC:PRKN, var("?")) -- path(DOID:"autosomal recessive Parkinson's disease 14")
p(HGNC:PRKN) -> bp(GO:"proteasomal protein catabolic process")
p(HGNC:PRKN, var("?")) -> bp(GO:"negative regulation of ubiquitin protein ligase activity")
bp(GO:"negative regulation of ubiquitin protein ligase activity") -> p(MESH:Proteins , pmod(CONSO:misfolded))
p(MESH:Proteins , pmod(CONSO:misfolded)) -> bp(CONSO:"protein aggregation")
UNSET Confidence
SET Evidence = "Parkin has been shown to be up-regulated via AFT4, following ER
stress and this event is associated with promotion of cell survival.
A reciprocal relationship was also shown between JNK and Parkin.
In addition, it was found that CHOP could down-regulate Parkin
expression [87]."
SET Confidence = "High"
bp(MESH:"Endoplasmic Reticulum Stress") -> p(HGNC:ATF4)
#AFT4 seems to be a typo. Replaced by ATF4
p(HGNC:ATF4) -> p(HGNC:PRKN)
p(HGNC:PRKN) -> bp(MESH:"Cell Survival")
bp(GO:"JNK cascade") neg p(HGNC:PRKN)
p(HGNC:DDIT3) -| g(HGNC:PRKN)
UNSET Confidence
SET Evidence = "However, prolonged stress will eventually
lead to cell death with mutant Parkin potentially tipping the balance
towards cell death [87]. More recently, the role of Parkin in
mitophagy (selective degradation of mitochondria via the
autophagy pathway) has been implicated in contributing to PD."
SET Confidence = "High"
p(HGNC:PRKN,var("?")) -> bp(MESH:"Cell Death")
bp(GO:mitophagy) -- p(HGNC:PRKN)
p(HGNC:PRKN) -- path(MESH:"Parkinson Disease")
UNSET Confidence
SET Evidence = "Parkin is recruited to depolarized
mitochondria via PTEN-induced kinase-1 (PINK1) leading to
mitophagy. It is proposed that Parkin then causes ubiquitination of
voltage-dependent anion channel 1 leading to mitochondrial clearance
[88]. Interestingly, disease-associated Parkin mutations disrupted
mitophagy at distinct steps highlighting the importance of
Parkin-mediated mitophagy in PD [88]."
SET Confidence = "High"
bp(GO:"mitochondrial depolarization") -> p(HGNC:PINK1)
p(HGNC:PINK1) -> p(HGNC:PRKN)
p(HGNC:PRKN) -> bp(GO:mitophagy)
p(HGNC:PRKN) -> p(HGNCGENEFAMILY:"Voltage dependent anion channels",pmod(Ub))
p(HGNCGENEFAMILY:"Voltage dependent anion channels",pmod(Ub)) -> bp(MESH:"Mitochondrial Degradation")
p(HGNC:PRKN,var("?")) -| bp(GO:"parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization")
bp(GO:"parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization") -- path(MESH:"Parkinson Disease")
UNSET Confidence
SET Evidence = "Mutations in PINK1 have also been implicated in the recessive
form of PD. Apart from its role in recruiting Parkin to mitochondria
for subsequent mitophagy, PINK1 has also been implicated in
protein stability and the wild-type protein may protect cells from
oxidative stress, mitochondrial dysfunction and apoptosis [89]."
SET Confidence = "High"
p(HGNC:PINK1,var("?")) -> path(DOID:"autosomal recessive Parkinson's disease 14")
p(HGNC:PINK1, var("?")) -- bp(MESH:"Protein Stability")
p(HGNC:PINK1) -| bp(MESH:"Oxidative Stress")
p(HGNC:PINK1) -| path(CONSO:"mitochondrial dysfunction")
p(HGNC:PINK1) -| bp(MESH:Apoptosis)
UNSET Confidence
SET Evidence = "Mutations in DJ-1 are also linked to PD. DJ-1 has been suggested
to act as an antioxidant or redox sensor protein and defective
DJ-1 may predispose to oxidative stress and activation of the ER
stress cascade [90]."
SET Confidence = "High"
p(HGNC:PARK7,var("?")) -- path(MESH:"Parkinson Disease")
p(HGNC:PARK7) -> bp(GO:"detection of redox state")
p(HGNC:PARK7,var("?")) -> bp(MESH:"Oxidative Stress")
p(HGNC:PARK7,var("?")) -> bp(MESH:"Endoplasmic Reticulum Stress")
UNSET Confidence