KEGG PATHWAY: map05016

PATHWAY: map05016

Entry

map05016                    Pathway

Name

Huntington disease

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

Pathway map

map05016

Huntington disease

Disease

H00059

Huntington disease

Reference

PMID:15459747

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)
DOI:10.1038/sj.embor.7400250

Reference

PMID:17041811

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)
DOI:10.1007/s00018-006-6242-0

Reference

PMID:18951640

Authors

Bossy-Wetzel E, Petrilli A, Knott AB

Title

Mutant huntingtin and mitochondrial dysfunction.

Journal

Trends Neurosci 31:609-16 (2008)
DOI:10.1016/j.tins.2008.09.004

Reference

PMID:16288298

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)
DOI:10.1038/nrn1806

Reference

PMID:15336977

Authors

Bezprozvanny I, Hayden MR

Title

Deranged neuronal calcium signaling and Huntington disease.

Journal

Biochem Biophys Res Commun 322:1310-7 (2004)
DOI:10.1016/j.bbrc.2004.08.035

Reference

PMID:14526190

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)
DOI:10.1159/000072864

Reference

PMID:12372277

Authors

Ross CA.

Title

Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders.

Journal

Neuron 35:819-22 (2002)
DOI:10.1016/S0896-6273(02)00872-3

Reference

PMID:15242639

Authors

Ross CA

Title

Huntington's disease: new paths to pathogenesis.

Journal

Cell 118:4-7 (2004)
DOI:10.1016/j.cell.2004.06.022

Reference

PMID:24739785

Authors

Coffey ET

Title

Nuclear and cytosolic JNK signalling in neurons.

Journal

Nat Rev Neurosci 15:285-99 (2014)
DOI:10.1038/nrn3729

Reference

PMID:19525941

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

Nat Neurosci 12:864-71 (2009)
DOI:10.1038/nn.2346

Reference

PMID:26920688

Authors

Kumar P, Kumar D, Jha SK, Jha NK, Ambasta RK

Title

Ion Channels in Neurological Disorders.

Journal

Adv Protein Chem Struct Biol 103:97-136 (2016)
DOI:10.1016/bs.apcsb.2015.10.006

Reference

PMID:25191533

Authors

Proft J, Weiss N

Title

Rectifying rectifier channels in Huntington disease.

Journal

Commun Integr Biol 7:e29410 (2014)
DOI:10.4161/cib.29410

Reference

PMID:15695335

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)
DOI:10.1073/pnas.0409402102

Reference

PMID:29427371

Authors

Mackay JP, Nassrallah WB, Raymond LA

Title

Cause or compensation?-Altered neuronal Ca(2+) handling in Huntington's disease.

Journal

CNS Neurosci Ther 24:301-310 (2018)
DOI:10.1111/cns.12817

Reference

PMID:11807533

Authors

Mattson MP.

Title

Accomplices to neuronal death.

Journal

Nature 415:377-9 (2002)
DOI:10.1038/415377a

Reference

PMID:17081970

Authors

McGill JK, Beal MF

Title

PGC-1alpha, a new therapeutic target in Huntington's disease?

Journal

Cell 127:465-8 (2006)
DOI:10.1016/j.cell.2006.10.023

Reference

PMID:30941017

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

Front Cell Neurosci 13:103 (2019)
DOI:10.3389/fncel.2019.00103

Reference

PMID:15996541

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)
DOI:10.1016/j.neuron.2005.06.023

Reference

PMID:11738471

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)
DOI:10.1016/S0197-0186(01)00059-6

Reference

PMID:15996546

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)
DOI:10.1016/j.neuron.2005.06.005

Reference

PMID:11839795

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)
DOI:10.1128/MCB.22.5.1277-1287.2002

Reference

PMID:25270767

Authors

Vidal RL, Matus S, Bargsted L, Hetz C

Title

Targeting autophagy in neurodegenerative diseases.

Journal

Trends Pharmacol Sci 35:583-91 (2014)
DOI:10.1016/j.tips.2014.09.002

Reference

PMID:16522639

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

J Biol Chem 281:14474-85 (2006)
DOI:10.1074/jbc.M600364200

Related
pathway

map00190

Oxidative phosphorylation

map03020

RNA polymerase

map03022

Basal transcription factors

map03050

Proteasome

map04020

Calcium signaling pathway

map04115

p53 signaling pathway

map04140

Autophagy - animal

map04141

Protein processing in endoplasmic reticulum

map04144

Endocytosis

map04210

Apoptosis

map04724

Glutamatergic synapse

KO pathway

ko05016

All links

Chemical substance (6)   
   KEGG COMPOUND (6)   
Gene (853004)   
   KEGG ORTHOLOGY (229)   
   RefGene (852775)   
Literature (23)   
   PubMed (23)   
All databases (853033)   

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