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Huntington’s Disease

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Neurotrophic Factors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 220))

Abstract

Changes in the level and activity of brain-derived neurotrophic factor (BDNF) have been described in a number of neurodegenerative disorders since early 1990s. However, only in Huntington disease (HD) gain- and loss-of-function experiments have mechanistically linked these abnormalities with the genetic defect.

In this chapter we will describe how huntingtin protein, whose mutation causes HD, is involved in the physiological control of BDNF synthesis and transport in neurons and how both processes are simultaneously disrupted in HD. We will describe the underlying molecular mechanisms and discuss pre-clinical data concerning the impact of the experimental manipulation of BDNF levels on HD progression. These studies have revealed that a major loss of BDNF protein in the brain of HD patients may contribute to the clinical manifestations of the disease. The experimental strategies under investigation to increase brain BDNF levels in animal models of HD will also be described, with a view to ultimately improving the clinical treatment of this condition.

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Abbreviations

3NP:

3-Nitropropionic acid

AAV:

Adeno-associated viral vector

ALS:

Amyotrophic lateral sclerosis

AMPA:

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BAC:

Bacterial-derived artificial chromosome

ARNT2:

Aryl hydrocarbon receptor nuclear translocator 2

BDNF:

Brain-derived neurotrophic factor

CaM kinase II:

α-Subunit of Ca2+/calmodulin-dependent kinase II

cAMP:

Cyclic adenosyne 3′ 5′ monophosphate

CaRE1/2/3:

Ca2+ Responsive element 1, 2 and 3

CaRF:

Calcium responsive transcription factor

CBP:

CREB Binding protein

C/EBP/beta:

CCAAT/Enhancer binding protein beta

ChIP:

Chromatin immunoprecipitation

CNS:

Central Nervous System

coREST:

REST Co-repressor 1

CRE:

cAMP/Ca2+ Responsive element

CREB:

CRE Binding protein

DARPP-32:

Dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa

DR:

Dietary restriction

ES:

Embryonic stem

ELISA:

Enzyme-linked immunosorbent assay

FDA:

Food and drug administration

GDNF:

Glial cell line-derived neurothrophic factor

Emx :

Empty spiracles homolog

eGFP:

Enhanced green fluorescent protein

GSK-3β:

Glycogen synthase kinase 3-beta

HAP1:

Huntingtin-associated protein 1

HDAC:

Histone deacetylase

HD:

Huntington’s disease

Hdh :

Huntington disease gene homolog

hsp70:

Heat shock protein cognate 70 kDa

HSJ1B:

Heat shock protein DNAJ-containing protein 1b

muHTT:

Mutant huntingtin

wtHTT:

Wild-type huntingtin

IT15 :

Interesting transcript 15

LiCl:

Lithium chloride

L-VDCC:

L-Type voltage-dependent Ca2+ channel

MEF2:

Myocyte enhancer factor-2

MeCP2:

Methyl-CpG binding protein 2

MEKK:

Mitogen-activated protein kinase kinase

MLK:

Mixed lineage kinase

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MSNs:

Medium sized spiny neurons

mTOR:

Mammalian target of rapamycin

NGF:

Nerve growth factor

NMDA:

N-Methyl-d-aspartic acid

NPAS4:

Neuronal PAS domain protein 4

p75NTR :

p75 Neurotrophin receptor

PCR:

Polymerase chain reaction

p150Glued :

150 kDa Dynein-associated polypeptide

PasRE:

Basic helix-loop-helix (bHLH)-PAS transcription factor response element

PGC-1alpha:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PKA:

Protein kinase A

Pro-BDNF:

BDNF Precursor

RE1/NRSE:

Repressor element 1/neuron-restrictive silencer element

REST/NRSF:

RE-1 Silencing transcription factor/neuron-restrictive silencer factor

RILP:

REST/NRSF-Interacting LIM domain protein

Sin3a:

Switch independent homologue 3a

SOX 11:

SRY (sex determining region Y)-box 11

Sp1:

Specificity protein 1

SSRIs:

Selective serotonin reuptake inhibitors

SVZ:

Subventricular zone

TAFII-130:

TATA box binding protein (TBP)-associated factor 130 kDa

TGases:

Transglutaminases

TrkB:

Tyrosine receptor kinase B

USF:

Upstream stimulatory factor

Val66Met:

Valine-to-methionine substitution at position 66

YAC:

Yeast-derived artificial chromosome

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Authors and Affiliations

  1. Department of Biosciences and Centre for Stem cell Research, Università degli Studi di Milano, Via Viotti 3/5, 20133, Milan, Italy

    Chiara Zuccato & Elena Cattaneo Ph.D.

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  1. Chiara Zuccato
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  2. Elena Cattaneo Ph.D.
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Correspondence to Chiara Zuccato or Elena Cattaneo Ph.D. .

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  1. Department of Neuroscience, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    Gary R. Lewin

  2. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Bruce D. Carter

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Zuccato, C., Cattaneo, E. (2014). Huntington’s Disease. In: Lewin, G., Carter, B. (eds) Neurotrophic Factors. Handbook of Experimental Pharmacology, vol 220. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-45106-5_14

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