Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disorder that primarily targets medium spiny neurons, leading to the gradual atrophy of the striatum. The disease affects 4.1–8.4 cases per 100,000 persons in the USA and Europe and typically displays relentless progression of cognitive and motor deficits over a period of 15–20 years. Its most striking clinical feature is the chorea: involuntary complex body movements involving the entire musculature with stereotyped patterns. HD is an autosomal dominant disorder caused by the expansion of an uninterrupted track of CAG repeats within exon 1 of the gene huntingtin (Htt). Htt codes for a soluble and multi-domain protein; the N-terminal fragment interacts with a wide variety of protein partners. Further, Htt contains several consensus sites for posttranslational modifications with significant functional roles, including protease cleavage, SUMOylation, ubiquitination, phosphorylation, palmitoylation, and acetylation. Notably, Htt displays functional pleiotropism, including prominent roles in gene transcription, endocytosis, intracellular trafficking, synaptic spine morphogenesis, apoptosis, and neural development. The abnormal trinucleotide expansion in the Htt gene product triggers a complex combination of gain- and loss-of-function pathological mechanisms that synergistically contribute to disease pathogenesis. Thus, HD pathogenesis may involve the interplay of multiple pathological cascades, including transcriptional dysregulation, neuronal excitotoxicity, impairments in the expression and delivery of neurotrophic factors, mitochondrial dysfunction, aberrant activation of proteases, and protein turnover, including aggregation. Indeed, it is likely that different pathological processes mediating progressive cellular dysfunction and late-onset cell death are operating in discrete brain regions in HD. The enormous strides that have been made in the understanding of the molecular pathogenesis of HD as well as in establishing emerging links between impairments in neural development and neuronal dysfunction have furnished the conceptual underpinnings and the novel molecular targets for devising innovative therapeutic strategies to prevent disease onset and to halt disease progression.
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Abbreviations
- 3-HK:
-
3-Hydroxykynurenine
- A2aRs:
-
Adenosine A2A Receptors
- Ac:
-
Acetylation
- Ago2:
-
Argonaute
- AMPA:
-
α-Amino-hydroxy-5-methyl-4-isoxazolepropionic acid
- APOE:
-
Apolipoprotein E
- BDNF:
-
Brain-derived neurotrophic factor
- BRN-2:
-
Brain-2
- CA150:
-
Coactivator of 150 kd
- CB1:
-
Cannabinoid receptor 1
- CB2:
-
Cannabinoid receptor 2
- CBP:
-
cAMP-response-element-binding protein-binding protein
- Cdk5:
-
Cyclin-dependent kinase 5
- CREB:
-
cAMP-response-element-binding protein
- CTBP:
-
C-terminal binding protein
- CTIP2:
-
COUP-TF-interacting protein 2
- DFFB:
-
Caspase-activated DNAse
- DRD1/2:
-
Dopamine receptors 1 and 2
- DRPLA:
-
Dentatorubral-pallidoluysian atrophy
- ENK:
-
Enkephalin
- ER:
-
Endoplasmic reticulum
- GASP2:
-
G-protein-coupled receptor-associated sorting protein 2
- GLT1:
-
Glutamate transporter
- GPe:
-
External aspect of the globus pallidus
- GPi:
-
Internal aspect of the globus pallidus
- Grb2:
-
Growth factor receptor-bound protein 2
- GRIK2:
-
Glur6 kainate glutamate receptor
- GRIN2A:
-
NR2A glutamate receptor subunit
- GRIN2B:
-
NR2B glutamate receptor subunit
- HAP1:
-
Htt-associated protein 1
- HAP1-KIF5:
-
Kinesin family motor protein 5
- HAP40:
-
Htt-associated protein 40
- HD:
-
Huntington’s disease
- HDAC:
-
Histone deacetylase
- HIP1:
-
Htt-interacting protein 1
- HIP14:
-
Htt-interacting protein 14
- Hippi:
-
HIP1 protein interactor
- HSG:
-
Huntington’s disease Study Group
- Htt:
-
Huntingtin
- IKK:
-
Ikappab kinase
- Insp(3)R1:
-
Inositol 1,4,5-trisphosphate receptor
- Kcnip1/2:
-
Kv-channel-interacting protein 1 and 2
- mGluRs:
-
Metabotropic glutamate receptors
- miRNAs:
-
Micro-RNAs
- MSN:
-
Medium-sized spiny neuron
- N-Cor1:
-
Nuclear receptor corepressor 1
- NES:
-
Nuclear export signal
- NeuroD:
-
Neuronal differentiation
- NF-kB:
-
Nuclear factor NF-kappa-B
- NF-Y:
-
Nuclear transcription factor-Y
- NMDA:
-
N-methyl-d-aspartate
- NO:
-
Nitric oxide
- NOS:
-
NO synthase
- NR1/2B:
-
NMDA receptor subunits 1 and 2B
- NRSF:
-
Neuron-restrictive silencing factor
- Oprk1:
-
Opioid receptor kappa 1
- Oprm1:
-
Opioid receptor mu 1
- P:
-
Phosphorylation
- P:
-
Polyproline
- p75ntr:
-
P75 neurotrophin receptors
- Pa:
-
Palmitoylation
- PACSIN1:
-
Protein kinase C and casein kinase substrate in neurons 1
- Pak2:
-
P21-activated kinase 2
- Penk1:
-
Proenkephalin 1
- PGC-1α:
-
Coactivator 1α
- PPAR-γ:
-
Peroxisome-proliferator-activated receptor γ
- PRC2:
-
Polycomb repressive complex 2
- Q:
-
Polyglutamine
- QA:
-
Quinolinic acid
- REST:
-
Repressor element 1-silencing transcription factor
- S:
-
SUMOylation
- SBMA:
-
Spinal and bulbar muscular atrophy
- SCA:
-
Spinocerebellar ataxia
- SNr:
-
Substantia nigra pars reticulation
- SP:
-
Substance P
- Sp1:
-
Specificity protein 1
- STN:
-
Subthalamic nucleus
- TAFII-130:
-
TATA-box-binding protein-associated factor II 130 Kda
- TCERG1:
-
Transcriptional coactivator CA150
- TP53:
-
Tumor suppressor p53
- TrkB:
-
Tyrosine kinase B
- Ub:
-
Ubiquitination
- UCHL1:
-
Ubiquitin carboxy-terminal hydrolase L1
- UHDRS:
-
Unified Huntington’s disease Rating Scale
- UTR:
-
Untranslated region
References
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Han I, You YM, Kordower JH et al (2010) Differential vulnerability of neurons in Huntington’s disease: the role of cell type-specific features. J Neurochem 113:1073
Molero AE, Gokhan S, Gonzalez S, Feig JL et al (2009) Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington’s disease. Proc Natl Acad Sci U S A 106:21900
Roos RA (2010) Huntington’s disease: a clinical review. Orphanet J Rare Dis 5(1):40
Ross CA, Tabrizi S (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83
Zuccato C, Valenza M, Cattaneo E (2010) Molecular mechanisms and potential therapeutic targets in Huntington’s disease. Physiol Rev 90:905
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Molero, A., Mehler, M.F. (2016). Huntington’s Disease. In: Pfaff, D., Volkow, N. (eds) Neuroscience in the 21st Century. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3474-4_113
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DOI: https://doi.org/10.1007/978-1-4939-3474-4_113
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