KEGG   PATHWAY: mmu05016Help
Entry
mmu05016                    Pathway                                

Name
Huntington's disease - Mus musculus (mouse)
Description
Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). The symptoms are choreiform, involuntary movements, personality changes and dementia. HD is caused by a CAG repeat expansion in the IT15gene, which results in a long stretch of polyglutamine close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. In the cytoplasm, full-length mHtt can interfere with BDNF vesicular transport on microtubules. This mutant protein also may lead to abnormal endocytosis and secretion in neurons, because normal Htt form a complex with the proteins Hip1, clathrin and AP2 that are involved in endocytosis. In addition, mHtt affects Ca2+ signaling by sensitizing InsP3R1 to activation by InsP3, stimulating NMDAR activity, and destabilizing mitochondrial Ca2+ handling. The mHtt translocates to the nucleus, where it forms intranuclear inclusions. Nuclear toxicity is believed to be caused by interference with gene transcription, leading to loss of transcription of neuroprotective molecules such as BDNF. While mHtt binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity. Augmented p53 mediates mitochondrial dysfunction.
Class
Human Diseases; Neurodegenerative diseases
BRITE hierarchy
Pathway map
Huntington's disease
mmu05016

All organismsOrtholog table
Module
RNA polymerase II, eukaryotes [PATH:mmu05016]
Organism
Mus musculus (mouse) [GN:mmu]
Gene
12757  
Clta; clathrin, light polypeptide (Lca) [KO:K04644]
74325  
Cltb; clathrin, light polypeptide (Lcb) [KO:K04645]
67300  
Cltc; clathrin, heavy polypeptide (Hc) [KO:K04646]
215114  
Hip1; huntingtin interacting protein 1 [KO:K04559]
11772  
Ap2a2; adaptor-related protein complex 2, alpha 2 subunit [KO:K11824]
11771  
Ap2a1; adaptor-related protein complex 2, alpha 1 subunit [KO:K11824]
71770  
Ap2b1; adaptor-related protein complex 2, beta 1 subunit [KO:K11825]
11773  
Ap2m1; adaptor-related protein complex 2, mu 1 subunit [KO:K11826]
232910  
Ap2s1; adaptor-related protein complex 2, sigma 1 subunit [KO:K11827]
15194  
Htt; huntingtin [KO:K04533]
73916  
Ift57; intraflagellar transport 57 [KO:K04638]
12370  
Casp8; caspase 8 [KO:K04398] [EC:3.4.22.61]
12367  
Casp3; caspase 3 [KO:K02187] [EC:3.4.22.56]
108071  
Grm5; glutamate receptor, metabotropic 5 [KO:K04604]
14682  
Gnaq; guanine nucleotide binding protein, alpha q polypeptide [KO:K04634]
18795  
Plcb1; phospholipase C, beta 1 [KO:K05858] [EC:3.1.4.11]
18797  
Plcb3; phospholipase C, beta 3 [KO:K05858] [EC:3.1.4.11]
18798  
Plcb4; phospholipase C, beta 4 [KO:K05858] [EC:3.1.4.11]
18796  
Plcb2; phospholipase C, beta 2 [KO:K05858] [EC:3.1.4.11]
14810  
Grin1; glutamate receptor, ionotropic, NMDA1 (zeta 1) [KO:K05208]
14812  
Grin2b; glutamate receptor, ionotropic, NMDA2B (epsilon 2) [KO:K05210]
16438  
Itpr1; inositol 1,4,5-trisphosphate receptor 1 [KO:K04958]
13385  
Dlg4; discs, large homolog 4 (Drosophila) [KO:K11828]
21817  
Tgm2; transglutaminase 2, C polypeptide [KO:K05625] [EC:2.3.2.13]
19712  
Rest; RE1-silencing transcription factor [KO:K09222]
20466  
Sin3a; transcriptional regulator, SIN3A (yeast) [KO:K11644]
217864  
Rcor1; REST corepressor 1 [KO:K11829]
15182  
Hdac2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
433759  
Hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
20020  
Polr2a; polymerase (RNA) II (DNA directed) polypeptide A [KO:K03006] [EC:2.7.7.6]
231329  
Polr2b; polymerase (RNA) II (DNA directed) polypeptide B [KO:K03010] [EC:2.7.7.6]
20021  
Polr2c; polymerase (RNA) II (DNA directed) polypeptide C [KO:K03011]
69241  
Polr2d; polymerase (RNA) II (DNA directed) polypeptide D [KO:K03012]
66420  
Polr2e; polymerase (RNA) II (DNA directed) polypeptide E [KO:K03013]
69833  
Polr2f; polymerase (RNA) II (DNA directed) polypeptide F [KO:K03014]
67710  
Polr2g; polymerase (RNA) II (DNA directed) polypeptide G [KO:K03015]
245841  
Polr2h; polymerase (RNA) II (DNA directed) polypeptide H [KO:K03016]
69920  
Polr2i; polymerase (RNA) II (DNA directed) polypeptide I [KO:K03017]
66491  
Polr2l; polymerase (RNA) II (DNA directed) polypeptide L [KO:K03007]
20022  
Polr2j; polymerase (RNA) II (DNA directed) polypeptide J [KO:K03008]
DNA-directed RNA polymerases I; K03009 DNA-directed RNA polymerases I, II, and III subunit RPABC4 [KO:K03009]
12064  
Bdnf; brain derived neurotrophic factor [KO:K04355]
13191  
Dctn1; dynactin 1 [KO:K04648]
69654  
Dctn2; dynactin 2 [KO:K10424]
67665  
Dctn4; dynactin 4 [KO:K10426]
15114  
Hap1; huntingtin-associated protein 1 [KO:K04647]
110084  
Dnah1; dynein, axonemal, heavy chain 1 [KO:K10408]
381917  
Dnah3; dynein, axonemal, heavy chain 3 [KO:K10408]
327954  
Dnah2; dynein, axonemal, heavy chain 2 [KO:K10408]
75563  
Dnali1; dynein, axonemal, light intermediate polypeptide 1 [KO:K10410]
68922  
Dnaic1; dynein, axonemal, intermediate chain 1 [KO:K10409]
432611  
Dnaic2; dynein, axonemal, intermediate chain 2 [KO:K11143]
105000  
Dnal1; dynein, axonemal, light chain 1 [KO:K10411]
54152  
Dnal4; dynein, axonemal, light chain 4 [KO:K10412]
12914  
Crebbp; CREB binding protein [KO:K04498] [EC:2.3.1.48]
328572  
Ep300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
72504  
Taf4b; TAF4B RNA polymerase II, TATA box binding protein (TBP)-associated factor [KO:K03129]
228980  
Taf4a; TAF4A RNA polymerase II, TATA box binding protein (TBP)-associated factor [KO:K03129]
21374  
Tbp; TATA box binding protein [KO:K03120]
237336  
Tbpl1; TATA box binding protein-like 1 [KO:K03120]
227606  
Tbpl2; TATA box binding protein like 2 [KO:K03120]
20683  
Sp1; trans-acting transcription factor 1 [KO:K04684]
12912  
Creb1; cAMP responsive element binding protein 1 [KO:K05870]
12913  
Creb3; cAMP responsive element binding protein 3 [KO:K09048]
26427  
Creb3l1; cAMP responsive element binding protein 3-like 1 [KO:K09048]
208647  
Creb3l2; cAMP responsive element binding protein 3-like 2 [KO:K09048]
208677  
Creb3l3; cAMP responsive element binding protein 3-like 3 [KO:K09048]
78284  
Creb3l4; cAMP responsive element binding protein 3-like 4 [KO:K09048]
231991  
Creb5; cAMP responsive element binding protein 5 [KO:K09047]
19017  
Ppargc1a; peroxisome proliferative activated receptor, gamma, coactivator 1 alpha [KO:K07202]
19016  
Pparg; peroxisome proliferator activated receptor gamma [KO:K08530]
21780  
Tfam; transcription factor A, mitochondrial [KO:K11830]
18181  
Nrf1; nuclear respiratory factor 1 [KO:K11831]
20655  
Sod1; superoxide dismutase 1, soluble [KO:K04565] [EC:1.15.1.1]
20656  
Sod2; superoxide dismutase 2, mitochondrial [KO:K04564] [EC:1.15.1.1]
22227  
Ucp1; uncoupling protein 1 (mitochondrial, proton carrier) [KO:K08769]
22059  
Trp53; transformation related protein 53 [KO:K04451]
12028  
Bax; BCL2-associated X protein [KO:K02159]
170770  
Bbc3; BCL2 binding component 3 [KO:K10132]
17995  
Ndufv1; NADH dehydrogenase (ubiquinone) flavoprotein 1 [KO:K03942] [EC:1.6.99.3 1.6.5.3]
72900  
Ndufv2; NADH dehydrogenase (ubiquinone) flavoprotein 2 [KO:K03943] [EC:1.6.99.3 1.6.5.3]
78330  
Ndufv3; NADH dehydrogenase (ubiquinone) flavoprotein 3 [KO:K03944]
54405  
Ndufa1; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1 [KO:K03945]
17991  
Ndufa2; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2 [KO:K03946]
66091  
Ndufa3; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 3 [KO:K03947]
17992  
Ndufa4; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4 [KO:K03948]
407790  
Ndufa4l2; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 [KO:K03948]
68202  
Ndufa5; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5 [KO:K03949]
67130  
Ndufa6; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6 (B14) [KO:K03950]
66416  
Ndufa7; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7 (B14.5a) [KO:K03951]
68375  
Ndufa8; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 [KO:K03952]
66108  
Ndufa9; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9 [KO:K03953]
67273  
Ndufa10; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 10 [KO:K03954]
70316  
Ndufab1; NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1 [KO:K03955]
239760  
Gm4943; predicted pseudogene 4943 [KO:K03956]
69875  
Ndufa11; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 11 [KO:K03956]
66414  
Ndufa12; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12 [KO:K11352]
67184  
Ndufa13; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13 [KO:K11353]
68198  
Ndufb2; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2 [KO:K03958]
66495  
Ndufb3; NADH dehydrogenase (ubiquinone) 1 beta subcomplex 3 [KO:K03959]
68194  
Ndufb4; NADH dehydrogenase (ubiquinone) 1 beta subcomplex 4 [KO:K03960]
Gm3873; predicted gene 3873 [KO:K03960]
Gm3244; predicted pseudogene 3244 [KO:K03960]
66046  
Ndufb5; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5 [KO:K03961]
230075  
Ndufb6; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6 [KO:K03962]
66916  
Ndufb7; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 7 [KO:K03963]
67264  
Ndufb8; NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 [KO:K03964]
66218  
Ndufb9; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9 [KO:K03965]
68342  
Ndufb10; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10 [KO:K03966]
104130  
Ndufb11; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11 [KO:K11351]
227197  
Ndufs1; NADH dehydrogenase (ubiquinone) Fe-S protein 1 [KO:K03934] [EC:1.6.99.3 1.6.5.3]
226646  
Ndufs2; NADH dehydrogenase (ubiquinone) Fe-S protein 2 [KO:K03935] [EC:1.6.99.3 1.6.5.3]
68349  
Ndufs3; NADH dehydrogenase (ubiquinone) Fe-S protein 3 [KO:K03936] [EC:1.6.99.3 1.6.5.3]
17993  
Ndufs4; NADH dehydrogenase (ubiquinone) Fe-S protein 4 [KO:K03937]
595136  
Ndufs5; NADH dehydrogenase (ubiquinone) Fe-S protein 5 [KO:K03938]
407785  
Ndufs6; NADH dehydrogenase (ubiquinone) Fe-S protein 6 [KO:K03939]
623286  
Gm6415; predicted pseudogene 6415 [KO:K03939]
75406  
Ndufs7; NADH dehydrogenase (ubiquinone) Fe-S protein 7 [KO:K03940] [EC:1.6.99.3 1.6.5.3]
225887  
Ndufs8; NADH dehydrogenase (ubiquinone) Fe-S protein 8 [KO:K03941] [EC:1.6.99.3 1.6.5.3]
66377  
Ndufc1; NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 1 [KO:K03967]
68197  
Ndufc2; NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2 [KO:K03968]
66945  
Sdha; succinate dehydrogenase complex, subunit A, flavoprotein (Fp) [KO:K00234] [EC:1.3.5.1]
67680  
Sdhb; succinate dehydrogenase complex, subunit B, iron sulfur (Ip) [KO:K00235] [EC:1.3.5.1]
66052  
Sdhc; succinate dehydrogenase complex, subunit C, integral membrane protein [KO:K00236]
66925  
Sdhd; succinate dehydrogenase complex, subunit D, integral membrane protein [KO:K00237]
66694  
Uqcrfs1; ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1 [KO:K00411] [EC:1.10.2.2]
17711  
CYTB; cytochrome b [KO:K00412]
66445  
Cyc1; cytochrome c-1 [KO:K00413]
22273  
Uqcrc1; ubiquinol-cytochrome c reductase core protein 1 [KO:K00414]
67003  
Uqcrc2; ubiquinol cytochrome c reductase core protein 2 [KO:K00415]
66576  
Uqcrh; ubiquinol-cytochrome c reductase hinge protein [KO:K00416]
67530  
Uqcrb; ubiquinol-cytochrome c reductase binding protein [KO:K00417]
22272  
Uqcrq; ubiquinol-cytochrome c reductase, complex III subunit VII [KO:K00418]
66152  
Uqcr10; ubiquinol-cytochrome c reductase, complex III subunit X [KO:K00419]
66594  
Uqcr11; ubiquinol-cytochrome c reductase, complex III subunit XI [KO:K00420]
17710  
COX3; cytochrome c oxidase subunit III [KO:K02262]
17708  
COX1; cytochrome c oxidase subunit I [KO:K02256] [EC:1.9.3.1]
17709  
COX2; cytochrome c oxidase subunit II [KO:K02261]
12857  
Cox4i1; cytochrome c oxidase subunit IV isoform 1 [KO:K02263]
84682  
Cox4i2; cytochrome c oxidase subunit IV isoform 2 [KO:K02263]
12858  
Cox5a; cytochrome c oxidase subunit Va [KO:K02264]
12859  
Cox5b; cytochrome c oxidase subunit Vb [KO:K02265]
12861  
Cox6a1; cytochrome c oxidase subunit VIa polypeptide 1 [KO:K02266]
12862  
Cox6a2; cytochrome c oxidase subunit VIa polypeptide 2 [KO:K02266]
110323  
Cox6b1; cytochrome c oxidase, subunit VIb polypeptide 1 [KO:K02267]
333182  
Cox6b2; cytochrome c oxidase subunit VIb polypeptide 2 [KO:K02267]
12864  
Cox6c; cytochrome c oxidase subunit VIc [KO:K02268]
12866  
Cox7a2; cytochrome c oxidase subunit VIIa 2 [KO:K02270]
12865  
Cox7a1; cytochrome c oxidase subunit VIIa 1 [KO:K02270]
20463  
Cox7a2l; cytochrome c oxidase subunit VIIa polypeptide 2-like [KO:K02270]
66142  
Cox7b; cytochrome c oxidase subunit VIIb [KO:K02271]
78174  
Cox7b2; cytochrome c oxidase subunit VIIb2 [KO:K02271]
12867  
Cox7c; cytochrome c oxidase subunit VIIc [KO:K02272]
12868  
Cox8a; cytochrome c oxidase subunit VIIIa [KO:K02273]
12869  
Cox8b; cytochrome c oxidase subunit VIIIb [KO:K02273]
75483  
Cox8c; cytochrome c oxidase subunit VIIIc [KO:K02273]
11946  
Atp5a1; ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 [KO:K02132]
11947  
Atp5b; ATP synthase, H+ transporting mitochondrial F1 complex, beta subunit [KO:K02133] [EC:3.6.3.14]
11949  
Atp5c1; ATP synthase, H+ transporting, mitochondrial F1 complex, gamma polypeptide 1 [KO:K02136]
66043  
Atp5d; ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunit [KO:K02134]
67126  
Atp5e; ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit [KO:K02135]
17705  
ATP6; ATP synthase F0 subunit 6 [KO:K02126]
11950  
Atp5f1; ATP synthase, H+ transporting, mitochondrial F0 complex, subunit B1 [KO:K02127]
11951  
Atp5g1; ATP synthase, H+ transporting, mitochondrial F0 complex, subunit C1 (subunit 9) [KO:K02128]
67942  
Atp5g2; ATP synthase, H+ transporting, mitochondrial F0 complex, subunit C2 (subunit 9) [KO:K02128]
228033  
Atp5g3; ATP synthase, H+ transporting, mitochondrial F0 complex, subunit C3 (subunit 9) [KO:K02128]
71679  
Atp5h; ATP synthase, H+ transporting, mitochondrial F0 complex, subunit D [KO:K02138]
28080  
Atp5o; ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit [KO:K02137]
11957  
Atp5j; ATP synthase, H+ transporting, mitochondrial F0 complex, subunit F [KO:K02131]
17706  
ATP8; ATP synthase F0 subunit 8 [KO:K02125]
22333  
Vdac1; voltage-dependent anion channel 1 [KO:K05862]
22334  
Vdac2; voltage-dependent anion channel 2 [KO:K15040]
22335  
Vdac3; voltage-dependent anion channel 3 [KO:K15041]
11739  
Slc25a4; solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 4 [KO:K05863]
11740  
Slc25a5; solute carrier family 25 (mitochondrial carrier, adenine nucleotide translocator), member 5 [KO:K05863]
73333  
Slc25a31; solute carrier family 25 (mitochondrial carrier [KO:K05863]
105675  
Ppif; peptidylprolyl isomerase F (cyclophilin F) [KO:K09565] [EC:5.2.1.8]
13063  
Cycs; cytochrome c, somatic [KO:K08738]
13067  
Cyct; cytochrome c, testis [KO:K08738]
11783  
Apaf1; apoptotic peptidase activating factor 1 [KO:K02084]
12371  
Casp9; caspase 9 [KO:K04399] [EC:3.4.22.62]
14775  
Gpx1; glutathione peroxidase 1 [KO:K00432] [EC:1.11.1.9]
Compound
C00025  
L-Glutamate
C00076  
Calcium cation
C01245  
D-myo-Inositol 1,4,5-trisphosphate
Reference
  Authors
Landles C, Bates GP
  Title
Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series.
  Journal
EMBO Rep 5:958-63 (2004)
Reference
  Authors
Borrell-Pages M, Zala D, Humbert S, Saudou F
  Title
Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies.
  Journal
Cell Mol Life Sci 63:2642-60 (2006)
Reference
  Authors
Bossy-Wetzel E, Petrilli A, Knott AB
  Title
Mutant huntingtin and mitochondrial dysfunction.
  Journal
Trends Neurosci 31:609-16 (2008)
Reference
  Authors
Cattaneo E, Zuccato C, Tartari M
  Title
Normal huntingtin function: an alternative approach to Huntington's disease.
  Journal
Nat Rev Neurosci 6:919-30 (2005)
Reference
  Authors
Bezprozvanny I, Hayden MR
  Title
Deranged neuronal calcium signaling and Huntington disease.
  Journal
Biochem Biophys Res Commun 322:1310-7 (2004)
Reference
  Authors
Sawa A, Tomoda T, Bae BI
  Title
Mechanisms of neuronal cell death in Huntington's disease.
  Journal
Cytogenet Genome Res 100:287-95 (2003)
Reference
  Authors
Ross CA.
  Title
Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders.
  Journal
Neuron 35:819-22 (2002)
Reference
  Authors
Ross CA
  Title
Huntington's disease: new paths to pathogenesis.
  Journal
Cell 118:4-7 (2004)
Reference
  Authors
Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinas R, Kristal BS, Hayden MR, Bezprozvanny I
  Title
Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease.
  Journal
Proc Natl Acad Sci U S A 102:2602-7 (2005)
Reference
  Authors
Mattson MP.
  Title
Accomplices to neuronal death.
  Journal
Nature 415:377-9 (2002)
Reference
  Authors
McGill JK, Beal MF
  Title
PGC-1alpha, a new therapeutic target in Huntington's disease?
  Journal
Cell 127:465-8 (2006)
Reference
  Authors
La Spada AR, Morrison RS
  Title
The power of the dark side: Huntington's disease protein and p53 form a deadly alliance.
  Journal
Neuron 47:1-3 (2005)
Reference
  Authors
Lesort M, Chun W, Tucholski J, Johnson GV
  Title
Does tissue transglutaminase play a role in Huntington's disease?
  Journal
Neurochem Int 40:37-52 (2002)
Reference
  Authors
Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward SD, Moran TH, Montell C, Ross CA, Snyder SH, Sawa A
  Title
p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease.
  Journal
Neuron 47:29-41 (2005)
Reference
  Authors
Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ
  Title
Interaction of Huntington disease protein with transcriptional activator Sp1.
  Journal
Mol Cell Biol 22:1277-87 (2002)
KO pathway
 

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