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Neuroinflammation in Huntington’s Disease

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Neuroinflammation and Neurodegeneration

Abstract

Huntington’s disease (HD) is a progressive, eventually terminal, neurodegenerative disease caused by autosomal-dominant mutations in the huntingtin gene (HTT). The early symptoms of HD typically include subtle changes in mood and/or cognition, as well as poor coordination and unsteady gait. These symptoms progressively worsen until coordinated movement is virtually impossible and mental abilities have declined to a state of dementia. There is no cure and patients generally succumb to comorbid complications within 20 years of onset. The mutation is an expansion of the CAG triplet repeat stretch in the HTT gene, resulting in an expanded poly-glutamine (polyQ) stretch in the huntingtin protein (HTT). The length of this CAG repeat correlates strongly with the age of onset as well as the rate of disease progression. The ability to identify at-risk individuals by genetic testing enabled researchers to conduct clinical studies and learn about early events in the development of HD. One of the earliest pathological changes observed in the CNS of HD patients is the appearance of neuroinflammation, preceding overt neurodegeneration or protein aggregation. Here we will review the data implicating neuroinflammation in all stages of HD, from initiation to progression. We will also explore the most recent advances in our understanding of neuroinflammation in HD including a potential role for the peripheral immune system. We will also discuss how these various biologies may lead the way to discovery of novel, innovative, and urgently needed therapies.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ApoE:

Apolipoprotein epsilon

ApoJ:

Apolipoprotein J

ATP:

Adenosine triphosphate

B cell:

Bone marrow-derived lymphocyte

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

CB2R:

Cannabinoid receptor 2

CCL5:

Chemokine (C–C motif) ligand 5 (also CCL5)

CNS:

Central nervous system

CXCL1:

Chemokine (C–X–C motif) ligand 1 (GROα, KC)

EAAT2:

Excitatory amino acid transporter 2

GABA:

Gama-aminobutyric acid (inhibitory neurotransmitter)

GFP:

Green fluorescent protein

HD:

Huntington’s disease

HTT:

Huntingtin’s protein

HTT :

Human huntingtin’s gene

Htt :

Mouse huntingtin’s gene

Iba1:

Ionized Ca2+-binding adapter molecule 1 [Allograft inflammatory factor 1 (AIF1)]

IKK:

IκB kinase

IL-10:

Interleukin 10

IL-4:

Interleukin 4

IL-6:

Interleukin 6

KCNN4:

K+ intermediate/small conductance Ca2+-activated channel, subfamily N, member 4

KMO:

Kynurenine 3-monooxygenase

LRP:

Lipoprotein receptor-related proteins

MCP-1:

Monocyte chemotactic protein-1 [Chemokine (C-C motif) ligand 2 (CCL2)]

MCP-4:

Monocyte chemotactic protein-4 [Chemokine (C–C motif) ligand 13 (CCL13)]

MIP-1β:

Macrophage inflammatory protein-1β, CCL4 [Chemokine (C-C motif) ligand 4]

MS:

Multiple sclerosis

NAD+ :

Nicotine adenine dinucleotide

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NMDA:

N-methyl-d-aspartate

NO:

Nitric oxide

P2X4:

P2X purinoceptor 4

P2X7:

P2X purinoceptor 7

PD:

Parkinson’s disease

PolyQ:

Poly-glutamine stretch

PrP:

Prion protein

Q:

Glutamine

RANTES:

Regulated on activation, normal T cell expressed and secreted

ROS:

Reactive oxygen species (superoxide, hydrogen peroxide, etc.)

SSRI:

Selective serotonin reuptake inhibitor

T cell:

Thymus-derived lymphocyte

TGF-β:

Transforming growth factor β

TLR4:

Toll-like receptor 4

TRPM2:

Transient receptor potential cation channel, subfamily M, member 2

VGCC:

Voltage-gated Ca2+ channels

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Authors and Affiliations

  1. Neuroinflammation Disease Biology Unit, Lundbeck Research USA, 215 College Road, Paramus, NJ, 07652, USA

    Roland G. W. Staal & Thomas Möller

Authors
  1. Roland G. W. Staal
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  2. Thomas Möller
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Correspondence to Roland G. W. Staal .

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Editors and Affiliations

  1. Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

    Phillip K. Peterson

  2. Department of Biochemistry Department of Molecular Biology, University of Miami School of Medicine, Miami, Florida, USA

    Michal Toborek

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Staal, R.G.W., Möller, T. (2014). Neuroinflammation in Huntington’s Disease. In: Peterson, P., Toborek, M. (eds) Neuroinflammation and Neurodegeneration. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1071-7_10

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