PATHWAY: mdo05016 Help
Entry
Name
Huntington disease - Monodelphis domestica (gray short-tailed opossum)
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 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.
Class
Human Diseases; Neurodegenerative disease
BRITE hierarchy
Pathway map
Ortholog table
Organism
Monodelphis domestica (gray short-tailed opossum) [GN:
mdo ]
Gene
100030198 AP2A1; adaptor related protein complex 2 alpha 1 subunit [KO:K11824 ]
100017800 AP2B1; adaptor related protein complex 2 beta 1 subunit [KO:K11825 ]
100011981 AP2M1; adaptor related protein complex 2 mu 1 subunit [KO:K11826 ]
100021079 AP2S1; adaptor related protein complex 2 sigma 1 subunit [KO:K11827 ]
100022923 ACTR1A; ARP1 actin-related protein 1 homolog A, centractin alpha [KO:K16575 ]
100024757 ACTR1B; ARP1 actin-related protein 1 homolog B, centractin beta [KO:K16575 ]
100023896 CACNA1B; calcium voltage-gated channel subunit alpha1 B [KO:K04849 ]
100023485 GRIN1; glutamate ionotropic receptor NMDA type subunit 1 [KO:K05208 ]
100017355 GRIN2B; glutamate ionotropic receptor NMDA type subunit 2B [KO:K05210 ]
100029673 GRIA1; glutamate ionotropic receptor AMPA type subunit 1 [KO:K05197 ]
100023645 GRIA2; glutamate ionotropic receptor AMPA type subunit 2 [KO:K05198 ]
100030019 GRIA3; glutamate ionotropic receptor AMPA type subunit 3 [KO:K05199 ]
100027109 GRIA4; glutamate ionotropic receptor AMPA type subunit 4 [KO:K05200 ]
100023256 KCNJ10; potassium voltage-gated channel subfamily J member 10 [KO:K05003 ]
100017208 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048 ]
100020067 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048 ]
100022547 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048 ]
100015046 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048 ]
100025091 PPARG; peroxisome proliferator activated receptor gamma [KO:K08530 ]
100030784 NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial-like [KO:K03939 ]
100020379 UQCRC1; cytochrome b-c1 complex subunit 1, mitochondrial [KO:K00414 ]
100026672 UQCRC2; cytochrome b-c1 complex subunit 2, mitochondrial [KO:K00415 ]
100013423 UQCR11; ubiquinol-cytochrome c reductase, complex III subunit XI [KO:K00420 ]
100018068 cytochrome c oxidase subunit 4 isoform 1, mitochondrial [KO:K02263 ]
103106696 cytochrome c oxidase subunit 4 isoform 2, mitochondrial [KO:K02263 ]
100032291 cytochrome c oxidase subunit 7A-related protein, mitochondrial [KO:K02270 ]
100014124 ATP5A1; ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1, cardiac muscle [KO:K02132 ]
100014350 ATP5B; ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide [KO:K02133 ] [EC:7.1.2.2 ]
100011414 ATP5C1; ATP synthase, H+ transporting, mitochondrial F1 complex, gamma polypeptide 1 [KO:K02136 ]
100022173 ATP5D; ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunit [KO:K02134 ]
100021402 ATP5E; ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit [KO:K02135 ]
100033122 ATP5F1; ATP synthase, H+ transporting, mitochondrial Fo complex subunit B1 [KO:K02127 ]
100018564 ATP5G1; ATP synthase, H+ transporting, mitochondrial Fo complex subunit C1 (subunit 9) [KO:K02128 ]
100018948 ATP5G3; ATP synthase, H+ transporting, mitochondrial Fo complex subunit C3 (subunit 9) [KO:K02128 ]
100023278 ATP5H; ATP synthase, H+ transporting, mitochondrial Fo complex subunit D [KO:K02138 ]
100026076 ATP5O; ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit [KO:K02137 ]
100022645 ATP5J; ATP synthase, H+ transporting, mitochondrial Fo complex subunit F6 [KO:K02131 ]
100015431 activating molecule in BECN1-regulated autophagy protein 1-like [KO:K17985 ]
100011149 WIPI2; WD repeat domain, phosphoinositide interacting 2 [KO:K17908 ]
100024500 WIPI1; WD repeat domain, phosphoinositide interacting 1 [KO:K17908 ]
Compound
C01245 D-myo-Inositol 1,4,5-trisphosphate
C04549 1-Phosphatidyl-1D-myo-inositol 3-phosphate
Reference
Authors
Landles C, Bates GP
Title
Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series.
Journal
Reference
Authors
Borrell-Pages M, Zala D, Humbert S, Saudou F
Title
Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies.
Journal
Reference
Authors
Bossy-Wetzel E, Petrilli A, Knott AB
Title
Mutant huntingtin and mitochondrial dysfunction.
Journal
Reference
Authors
Cattaneo E, Zuccato C, Tartari M
Title
Normal huntingtin function: an alternative approach to Huntington's disease.
Journal
Reference
Authors
Bezprozvanny I, Hayden MR
Title
Deranged neuronal calcium signaling and Huntington disease.
Journal
Reference
Authors
Sawa A, Tomoda T, Bae BI
Title
Mechanisms of neuronal cell death in Huntington's disease.
Journal
Reference
Authors
Ross CA.
Title
Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders.
Journal
Reference
Authors
Ross CA
Title
Huntington's disease: new paths to pathogenesis.
Journal
Reference
Authors
Coffey ET
Title
Nuclear and cytosolic JNK signalling in neurons.
Journal
Reference
Authors
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
Title
Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin.
Journal
Reference
Authors
Kumar P, Kumar D, Jha SK, Jha NK, Ambasta RK
Title
Ion Channels in Neurological Disorders.
Journal
Reference
Authors
Proft J, Weiss N
Title
Rectifying rectifier channels in Huntington disease.
Journal
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
Reference
Authors
Mackay JP, Nassrallah WB, Raymond LA
Title
Cause or compensation?-Altered neuronal Ca(2+) handling in Huntington's disease.
Journal
Reference
Authors
Mattson MP.
Title
Accomplices to neuronal death.
Journal
Reference
Authors
McGill JK, Beal MF
Title
PGC-1alpha, a new therapeutic target in Huntington's disease?
Journal
Reference
Authors
Intihar TA, Martinez EA, Gomez-Pastor R
Title
Mitochondrial Dysfunction in Huntington's Disease; Interplay Between HSF1, p53 and PGC-1alpha Transcription Factors.
Journal
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
Reference
Authors
Lesort M, Chun W, Tucholski J, Johnson GV
Title
Does tissue transglutaminase play a role in Huntington's disease?
Journal
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
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
Reference
Authors
Vidal RL, Matus S, Bargsted L, Hetz C
Title
Targeting autophagy in neurodegenerative diseases.
Journal
Reference
Authors
Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, MacDonald M, Yankner B, Yuan J
Title
Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1.
Journal
Related pathway
mdo04141 Protein processing in endoplasmic reticulum
KO pathway