Abstract
Huntington’s disease (HD) is a tandem repeat disorder involving neurodegeneration and a complex combination of symptoms. These include psychiatric symptoms, cognitive deficits culminating in dementia, and the movement disorder epitomised by motor signs such as chorea. HD is caused by a CAG repeat expansion encoding an extended tract of the amino acid glutamine in the huntingtin protein. This polyglutamine expansion appears to induce a ‘change of function’, possibly a ‘gain of function’, in the huntingtin protein, which leads to various molecular and cellular cascades of pathogenesis. In the current review, we will briefly describe these broader aspects of HD pathogenesis, but will then focus on specific aspects where there are substantial bodies of experimental evidence, including oxidative stress, mitochondrial dysfunction, glutamatergic dysfunction and neuroinflammation. Furthermore, we will review recent preclinical therapeutic approaches targeting some of these pathogenic pathways, their clinical implications and future directions.
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Abbreviations
- 3-NP:
-
3-Nitropropionic acid
- ADP/ATP:
-
Adenosine diphosphate/adenosine triphosphate
- BAC:
-
Bacterial artificial chromosome
- BDNF:
-
Brain-derived neurotrophic factor
- CBP:
-
CREB-binding protein
- CI:
-
Cytoplasmic inclusions
- CNS:
-
Central nervous system
- CREB:
-
cAMP response element binding protein
- CSE:
-
Cystathionine ϒ-ligase
- D1/D2:
-
Dopamine receptor 1/2
- DCF:
-
Dichlorofluorescin
- Drp-1:
-
Dynamin-related protein-1
- EAAC1:
-
Excitatory amino acid carrier 1
- ERK:
-
Extracellular signal-regulated kinases
- ES:
-
Human embryonic stem cells
- ETC:
-
Electron transport chain
- FOXO:
-
Forkhead box protein o
- GLAST:
-
Glutamate transporter protein
- GLT-1:
-
Glutamate transporter 1
- GluNx:
-
NMDA glutamate receptor x
- GPe:
-
External globus pallidus
- GPx:
-
Glutathione peroxidase
- GR:
-
Glutathione reductase
- GSH:
-
Glutathione
- GSSG:
-
Glutathione disulphide (oxidised glutathione)
- HAPx:
-
Huntingtin-associated protein x
- HD:
-
Huntington’s disease
- HTT:
-
Huntingtin
- IDO:
-
Indolamine dioxygenase
- iPS:
-
Inducible pluripotent stem cells
- LPS:
-
Lipopolysaccharides
- MAP:
-
Microtubule-associated motor proteins
- mGluRx:
-
Metabotropic glutamate receptor x
- mHTT:
-
Mutant huntingtin
- MMP3:
-
Matrix metalloprotease 3
- MSN:
-
Medium spiny neuron
- NAC:
-
N-Acetylcysteine
- N-Cor:
-
Nuclear receptor co-repressor
- NDGA:
-
Nordihydroguaiaretic acid
- NI:
-
Nuclear inclusions
- NMDAR:
-
NMDA receptor
- NRF-x:
-
Nuclear respiratory factor-x
- NRSF:
-
Neuron restrictive silencer factor
- OXPHOS:
-
Oxidative phosphorylation
- PGC-1α:
-
PPAR-ϒ coactivator-1α
- polyQ:
-
Polyglutamine
- PPAR:
-
Peroxisome proliferator-activated receptor
- QA:
-
Quinolinic acid
- REST:
-
RE1-silencing transcription factor
- ROS:
-
Reactive oxygen species
- SN:
-
Subthalamic nucleus
- Sp1:
-
Specificity binding protein 1
- TIMx:
-
Translocase of the inner mitochondrial membrane complex x
- TNF-x:
-
Tumour necrosis factor-x
- TOM:
-
Translocase of the outer mitochondrial membrane complex
- xCT:
-
Light chain of system xc− transporter complex
- YAC:
-
Yeast artificial chromosome
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Wright, D.J., Renoir, T., Gray, L.J., Hannan, A.J. (2017). Huntington’s Disease: Pathogenic Mechanisms and Therapeutic Targets. In: Beart, P., Robinson, M., Rattray, M., Maragakis, N. (eds) Neurodegenerative Diseases. Advances in Neurobiology, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-57193-5_4
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DOI: https://doi.org/10.1007/978-3-319-57193-5_4
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