KEGG   PATHWAY: ko05016
ko05016                     Pathway                                

Huntington disease
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 IT15 gene, which results in a long stretch of polyglutamine (polyQ) close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. Full-length huntingtin is cleaved by proteases in the cytoplasm, leading to the formation of cytoplasmic and neuritic aggregates. mHtt also alters vesicular transport and recycling, causes cytosolic and mitochondrial Ca2+  overload, triggers endoplasmic reticulum stress through proteasomal dysfunction, and impairs autophagy function, increasing neuronal death susceptibility. N-terminal fragments containing the polyQ strech translocate to the nucleus where they impair transcription and induce neuronal death.
Human Diseases; Neurodegenerative disease
Pathway map
ko05016  Huntington disease

H00059  Huntington disease
K04644  clathrin light chain A
K04645  clathrin light chain B
K04646  clathrin heavy chain
K04559  huntingtin interacting protein 1
K11824  AP-2 complex subunit alpha
K11825  AP-2 complex subunit beta-1
K11826  AP-2 complex subunit mu-1
K11827  AP-2 complex subunit sigma-1
K04533  huntingtin
K04648  dynactin 1
K10424  dynactin 2
K10425  dynactin 3
K10426  dynactin 4
K10427  dynactin 5
K10428  dynactin 6
K16575  centractin
K16576  actin-related protein 10
K04647  huntingtin-associated protein 1
K10408  dynein heavy chain, axonemal
K10410  dynein light intermediate chain, axonemal
K10409  dynein intermediate chain 1, axonemal
K11143  dynein intermediate chain 2, axonemal
K10411  dynein light chain 1, axonemal
K10412  dynein light chain 4, axonemal
K07374  tubulin alpha
K07375  tubulin beta
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:]
K10396  kinesin family member 5
K10407  kinesin light chain
K04638  intraflagellar transport protein 57
K04398  caspase 8 [EC:]
K02187  caspase 3 [EC:]
K04604  metabotropic glutamate receptor 5
K04634  guanine nucleotide-binding protein G(q) subunit alpha
K05858  phosphatidylinositol phospholipase C, beta [EC:]
K04560  syntaxin 1A
K04849  voltage-dependent calcium channel N type alpha-1B
K05208  glutamate receptor ionotropic, NMDA 1
K05210  glutamate receptor ionotropic, NMDA 2B
K04958  inositol 1,4,5-triphosphate receptor type 1
K11828  discs large protein 4
K05197  glutamate receptor 1
K05198  glutamate receptor 2
K05199  glutamate receptor 3
K05200  glutamate receptor 4
K05625  transglutaminase 2 [EC:]
K05614  solute carrier family 1 (glial high affinity glutamate transporter), member 3
K05613  solute carrier family 1 (glial high affinity glutamate transporter), member 2
K05003  potassium inwardly-rectifying channel subfamily J member 10
K09222  RE1-silencing transcription factor
K11644  paired amphipathic helix protein Sin3a
K11829  REST corepressor 1
K06067  histone deacetylase 1/2 [EC:]
K03006  DNA-directed RNA polymerase II subunit RPB1 [EC:]
K03010  DNA-directed RNA polymerase II subunit RPB2 [EC:]
K03011  DNA-directed RNA polymerase II subunit RPB3
K03012  DNA-directed RNA polymerase II subunit RPB4
K03013  DNA-directed RNA polymerases I, II, and III subunit RPABC1
K03014  DNA-directed RNA polymerases I, II, and III subunit RPABC2
K03015  DNA-directed RNA polymerase II subunit RPB7
K03016  DNA-directed RNA polymerases I, II, and III subunit RPABC3
K03017  DNA-directed RNA polymerase II subunit RPB9
K03007  DNA-directed RNA polymerases I, II, and III subunit RPABC5
K03008  DNA-directed RNA polymerase II subunit RPB11
K03009  DNA-directed RNA polymerases I, II, and III subunit RPABC4
K04355  brain-derived neurotrophic factor
K04498  E1A/CREB-binding protein [EC:]
K03129  transcription initiation factor TFIID subunit 4
K03120  transcription initiation factor TFIID TATA-box-binding protein
K04684  transcription factor Sp1
K05870  cyclic AMP-responsive element-binding protein 1
K09048  cyclic AMP-responsive element-binding protein 3
K09047  cyclic AMP-responsive element-binding protein 5
K07202  alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha
K08530  peroxisome proliferator-activated receptor gamma
K11830  transcription factor A, mitochondrial
K11831  nuclear respiratory factor 1
K04565  superoxide dismutase, Cu-Zn family [EC:]
K04564  superoxide dismutase, Fe-Mn family [EC:]
K00432  glutathione peroxidase [EC:]
K08769  solute carrier family 25 (mitochondrial uncoupling protein), member 7
K04451  tumor protein p53
K02159  apoptosis regulator BAX
K10132  Bcl-2-binding component 3
K03878  NADH-ubiquinone oxidoreductase chain 1 [EC:]
K03879  NADH-ubiquinone oxidoreductase chain 2 [EC:]
K03880  NADH-ubiquinone oxidoreductase chain 3 [EC:]
K03881  NADH-ubiquinone oxidoreductase chain 4 [EC:]
K03882  NADH-ubiquinone oxidoreductase chain 4L [EC:]
K03883  NADH-ubiquinone oxidoreductase chain 5 [EC:]
K03884  NADH-ubiquinone oxidoreductase chain 6 [EC:]
K03942  NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:]
K03943  NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:]
K03944  NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955  NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1, acyl-carrier protein
K03956  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K11352  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K03957  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K11351  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K03934  NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:]
K03935  NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:]
K03936  NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:]
K03937  NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938  NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939  NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940  NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:]
K03941  NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:]
K03967  NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968  NADH dehydrogenase (ubiquinone) 1 subunit C2
K00234  succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:]
K00235  succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:]
K00236  succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237  succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411  ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:]
K00412  ubiquinol-cytochrome c reductase cytochrome b subunit
K00413  ubiquinol-cytochrome c reductase cytochrome c1 subunit
K00414  ubiquinol-cytochrome c reductase core subunit 1
K00415  ubiquinol-cytochrome c reductase core subunit 2
K00416  ubiquinol-cytochrome c reductase subunit 6
K00417  ubiquinol-cytochrome c reductase subunit 7
K00418  ubiquinol-cytochrome c reductase subunit 8
K00419  ubiquinol-cytochrome c reductase subunit 9
K00420  ubiquinol-cytochrome c reductase subunit 10
K02262  cytochrome c oxidase subunit 3
K02256  cytochrome c oxidase subunit 1 [EC:]
K02261  cytochrome c oxidase subunit 2
K02263  cytochrome c oxidase subunit 4
K02264  cytochrome c oxidase subunit 5a
K02265  cytochrome c oxidase subunit 5b
K02266  cytochrome c oxidase subunit 6a
K02267  cytochrome c oxidase subunit 6b
K02268  cytochrome c oxidase subunit 6c
K02270  cytochrome c oxidase subunit 7a
K02271  cytochrome c oxidase subunit 7b
K02272  cytochrome c oxidase subunit 7c
K02273  cytochrome c oxidase subunit 8
K02132  F-type H+-transporting ATPase subunit alpha
K02133  F-type H+-transporting ATPase subunit beta [EC:]
K02136  F-type H+-transporting ATPase subunit gamma
K02134  F-type H+-transporting ATPase subunit delta
K02135  F-type H+-transporting ATPase subunit epsilon
K02126  F-type H+-transporting ATPase subunit a
K02127  F-type H+-transporting ATPase subunit b
K02128  F-type H+-transporting ATPase subunit c
K02138  F-type H+-transporting ATPase subunit d
K02137  F-type H+-transporting ATPase subunit O
K02131  F-type H+-transporting ATPase subunit 6
K02125  F-type H+-transporting ATPase subunit 8
K05862  voltage-dependent anion channel protein 1
K15040  voltage-dependent anion channel protein 2
K15041  voltage-dependent anion channel protein 3
K05863  solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31
K09565  peptidyl-prolyl isomerase F (cyclophilin D) [EC:]
K08738  cytochrome c
K02084  apoptotic protease-activating factor
K04399  caspase 9 [EC:]
K02730  20S proteasome subunit alpha 1 [EC:]
K02726  20S proteasome subunit alpha 2 [EC:]
K02728  20S proteasome subunit alpha 3 [EC:]
K02731  20S proteasome subunit alpha 4 [EC:]
K02729  20S proteasome subunit alpha 5 [EC:]
K02725  20S proteasome subunit alpha 6 [EC:]
K02727  20S proteasome subunit alpha 7 [EC:]
K02738  20S proteasome subunit beta 1 [EC:]
K02739  20S proteasome subunit beta 2 [EC:]
K02735  20S proteasome subunit beta 3 [EC:]
K02734  20S proteasome subunit beta 4 [EC:]
K02737  20S proteasome subunit beta 5 [EC:]
K02732  20S proteasome subunit beta 6 [EC:]
K02736  20S proteasome subunit beta 7 [EC:]
K03061  26S proteasome regulatory subunit T1
K03062  26S proteasome regulatory subunit T2
K03063  26S proteasome regulatory subunit T3
K03064  26S proteasome regulatory subunit T4
K03065  26S proteasome regulatory subunit T5
K03066  26S proteasome regulatory subunit T6
K03028  26S proteasome regulatory subunit N1
K03032  26S proteasome regulatory subunit N2
K03033  26S proteasome regulatory subunit N3
K06693  26S proteasome regulatory subunit N4
K03035  26S proteasome regulatory subunit N5
K03036  26S proteasome regulatory subunit N6
K03037  26S proteasome regulatory subunit N7
K03038  26S proteasome regulatory subunit N8
K03039  26S proteasome regulatory subunit N9
K03029  26S proteasome regulatory subunit N10
K03030  26S proteasome regulatory subunit N11
K03031  26S proteasome regulatory subunit N12
K06691  26S proteasome regulatory subunit N13
K10881  26 proteasome complex subunit DSS1
K04418  mitogen-activated protein kinase kinase kinase 10 [EC:]
K08852  serine/threonine-protein kinase/endoribonuclease IRE1 [EC: 3.1.26.-]
K03173  TNF receptor-associated factor 2 [EC:]
K04426  mitogen-activated protein kinase kinase kinase 5 [EC:]
K04431  mitogen-activated protein kinase kinase 7 [EC:]
K07203  serine/threonine-protein kinase mTOR [EC:]
K21357  serine/threonine-protein kinase ULK1 [EC:]
K08269  serine/threonine-protein kinase ULK2 [EC:]
K19730  autophagy-related protein 101
K08331  autophagy-related protein 13
K17589  RB1-inducible coiled-coil protein 1
K17985  activating molecule in BECN1-regulated autophagy protein 1
K08334  beclin
K08333  phosphoinositide-3-kinase, regulatory subunit 4 [EC:]
K17889  beclin 1-associated autophagy-related key regulator
K21246  nuclear receptor-binding factor 2
K00914  phosphatidylinositol 3-kinase [EC:]
K17906  autophagy-related protein 2
K17908  autophagy-related protein 18
C00025  L-Glutamate
C00076  Calcium cation
C00238  Potassium cation
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C04549  1-Phosphatidyl-1D-myo-inositol 3-phosphate
Landles C, Bates GP
Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series.
EMBO Rep 5:958-63 (2004)
Borrell-Pages M, Zala D, Humbert S, Saudou F
Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies.
Cell Mol Life Sci 63:2642-60 (2006)
Bossy-Wetzel E, Petrilli A, Knott AB
Mutant huntingtin and mitochondrial dysfunction.
Trends Neurosci 31:609-16 (2008)
Cattaneo E, Zuccato C, Tartari M
Normal huntingtin function: an alternative approach to Huntington's disease.
Nat Rev Neurosci 6:919-30 (2005)
Bezprozvanny I, Hayden MR
Deranged neuronal calcium signaling and Huntington disease.
Biochem Biophys Res Commun 322:1310-7 (2004)
Sawa A, Tomoda T, Bae BI
Mechanisms of neuronal cell death in Huntington's disease.
Cytogenet Genome Res 100:287-95 (2003)
Ross CA.
Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders.
Neuron 35:819-22 (2002)
Ross CA
Huntington's disease: new paths to pathogenesis.
Cell 118:4-7 (2004)
Coffey ET
Nuclear and cytosolic JNK signalling in neurons.
Nat Rev Neurosci 15:285-99 (2014)
Morfini GA, You YM, Pollema SL, Kaminska A, Liu K, Yoshioka K, Bjorkblom B, Coffey ET, Bagnato C, Han D, Huang CF, Banker G, Pigino G, Brady ST
Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin.
Nat Neurosci 12:864-71 (2009)
Kumar P, Kumar D, Jha SK, Jha NK, Ambasta RK
Ion Channels in Neurological Disorders.
Adv Protein Chem Struct Biol 103:97-136 (2016)
Proft J, Weiss N
Rectifying rectifier channels in Huntington disease.
Commun Integr Biol 7:e29410 (2014)
Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinas R, Kristal BS, Hayden MR, Bezprozvanny I
Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease.
Proc Natl Acad Sci U S A 102:2602-7 (2005)
Mackay JP, Nassrallah WB, Raymond LA
Cause or compensation?-Altered neuronal Ca(2+) handling in Huntington's disease.
CNS Neurosci Ther 24:301-310 (2018)
Mattson MP.
Accomplices to neuronal death.
Nature 415:377-9 (2002)
McGill JK, Beal MF
PGC-1alpha, a new therapeutic target in Huntington's disease?
Cell 127:465-8 (2006)
Intihar TA, Martinez EA, Gomez-Pastor R
Mitochondrial Dysfunction in Huntington's Disease; Interplay Between HSF1, p53 and PGC-1alpha Transcription Factors.
Front Cell Neurosci 13:103 (2019)
La Spada AR, Morrison RS
The power of the dark side: Huntington's disease protein and p53 form a deadly alliance.
Neuron 47:1-3 (2005)
Lesort M, Chun W, Tucholski J, Johnson GV
Does tissue transglutaminase play a role in Huntington's disease?
Neurochem Int 40:37-52 (2002)
Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward SD, Moran TH, Montell C, Ross CA, Snyder SH, Sawa A
p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease.
Neuron 47:29-41 (2005)
Li SH, Cheng AL, Zhou H, Lam S, Rao M, Li H, Li XJ
Interaction of Huntington disease protein with transcriptional activator Sp1.
Mol Cell Biol 22:1277-87 (2002)
Vidal RL, Matus S, Bargsted L, Hetz C
Targeting autophagy in neurodegenerative diseases.
Trends Pharmacol Sci 35:583-91 (2014)
Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, MacDonald M, Yankner B, Yuan J
Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1.
J Biol Chem 281:14474-85 (2006)
ko00190  Oxidative phosphorylation
ko03020  RNA polymerase
ko03022  Basal transcription factors
ko03050  Proteasome
ko04020  Calcium signaling pathway
ko04115  p53 signaling pathway
ko04140  Autophagy - animal
ko04141  Protein processing in endoplasmic reticulum
ko04144  Endocytosis
ko04210  Apoptosis
ko04724  Glutamatergic synapse

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