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Huntington’s Disease: Pathogenic Mechanisms and Therapeutic Targets

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Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 15))

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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Authors and Affiliations

  1. Faculty of Health, School of Medicine, Deakin University, Locked Bag 20000, Geelong, VIC, 3220, Australia

    Dean J. Wright Ph.D. & Laura J. Gray Ph.D.

  2. Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Pde, Parkville, VIC, 3010, Australia

    Dean J. Wright Ph.D., Thibault Renoir Ph.D., Laura J. Gray Ph.D. & Anthony J. Hannan Ph.D.

  3. Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia

    Anthony J. Hannan Ph.D.

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  1. Dean J. Wright Ph.D.
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  2. Thibault Renoir Ph.D.
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  3. Laura J. Gray Ph.D.
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  4. Anthony J. Hannan Ph.D.
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Correspondence to Anthony J. Hannan Ph.D. .

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  1. University of Melbourne Florey Institute of Neuroscience and Mental Health, Parkville, Australia

    Philip Beart

  2. Pediatrics and Pharmacology Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael Robinson

  3. School of Life Sciences Bradford School of Pharmacy, University of Bradford, Bradford, United Kingdom

    Marcus Rattray

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Nicholas J. Maragakis

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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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