Molecular Targets and Therapeutic Strategies in Huntingtons Disease

Rego, A. Cristina; Almeida, Luís Pereira de

doi:10.2174/1568007054546081

Cited by 20 publications

(11 citation statements)

References 283 publications

(366 reference statements)

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“…Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary body movements, cognitive deficits, and changes in personality [297-299]. Symptoms generally start appearing between mid thirties and middle age, and patients usually die 15 to 20 years after the symptomatic onset [297,299].…”

Section: Huntington’s Diseasementioning

confidence: 99%

“…Symptoms generally start appearing between mid thirties and middle age, and patients usually die 15 to 20 years after the symptomatic onset [297,299]. The neurodegeneration occurs preferentially in the striatum, extends at later stages to other brain regions including the deep layers of cortex, globus pallidus, thalamus, subthalamic nuclei, substantia nigra and gliosis formation appears [297]. In the striatum, the neuronal loss selectively affects GABAergic medium spiny neurons, whereas large aspiny cholinergic neurons are spared [297,299].…”

Section: Huntington’s Diseasementioning

confidence: 99%

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Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

Hovelsø

Sotty²,

Montezinho³

et al. 2012

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Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer’s disease and pain.

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Section: Huntington’s Diseasementioning

confidence: 99%

Section: Huntington’s Diseasementioning

confidence: 99%

Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

Hovelsø

Sotty²,

Montezinho³

et al. 2012

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“…Moreover, there is an inverse correlation between the age of onset and the higher length of polyQ expansion, whereby more CAG repeats is associated with an earlier disease onset (Andrew et al , 1993 ). However, this only accounts for approximately 40 % of the variation, with remaining features probably due to genetic polymorphisms adjacent to CAG repeats (e.g., Rego and de Almeida , 2005 ) and/or environmental factors (van Dellen and Hannan , 2004 ). There are interesting candidate genes responsible for the variance on the age of onset, such as genes encoding for NR2A/B receptor subunits of the N -methyl-d -aspartate receptor (Arning et al , 2005 ), glucocorticoid regulated kinase, metabotropic glutamate receptor and E3 ubiquitin-protein ligase (Li et al , 2006 ).…”

Section: Overview Of Huntington ' S Disease Genetics and Neuropatholomentioning

confidence: 99%

Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q

Naia¹,

Ribeiro²,

Rego³

2011

Revneuro

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Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion of CAG repeats in the HD gene encoding for huntingtin (Htt), resulting in progressive death of striatal neurons, with clinical symptoms of chorea, dementia and dramatic weight loss. Metabolic and mitochondrial dysfunction caused by the expanded polyglutamine sequence have been described along with other mechanisms of neurodegeneration previously described in human tissues and animal models of HD. In this review, we focus on mitochondrial and metabolic disturbances affecting both the central nervous system and peripheral cells, including mitochondrial DNA damage, mitochondrial complexes defects, loss of calcium homeostasis and transcriptional deregulation. Glucose abnormalities have also been described in peripheral tissues of HD patients and in HD animal and cellular models. Moreover, there are no effective neuroprotective treatments available in HD. Thus, we briefly discuss the role of creatine and coenzyme Q10 that target mitochondrial dysfunction and impaired bioenergetics and have been previously used in HD clinical trials.

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“…It is well known that glutamate plays an important role in neuronal excitotoxicity through the activation of ionotropic receptors [11,19,121]. Excitotoxicity is one of the most extensively studied processes of neuronal cell death, and plays an important role in many CNS disorders, including ischemia, trauma, and neurodegenerative disorders, such as AD, HD, Parkinson's disease, and amyotrophic lateral sclerosis [122][123][124][125][126][127][128]. Excitotoxicity is characterized by an excessive synaptic release of glutamate, leading to glutamate receptor over-stimulation and Ca 2+ overload, compromising mitochondria function and leading to cell death [129,130].…”

Section: Role Of Glutamate Receptors In Neuronal Survival In Hdmentioning

confidence: 99%

Huntington’s Disease and Group I Metabotropic Glutamate Receptors

2010

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary body movement, cognitive impairment and psychiatric disturbance. A polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein is the genetic cause of HD. Htt protein interacts with a wide variety of proteins, and htt mutation causes cell signaling alterations in various neurotransmitter systems, including dopaminergic, glutamatergic, and cannabinoid systems, as well as trophic factor systems. This review will overview recent findings concerning htt-promoted alterations in cell signaling that involve different neurotransmitters and trophic factor systems, especially involving mGluR1/5, as glutamate plays a crucial role in neuronal cell death. The neuronal cell death that takes place in the striatum and cortex of HD patients is the most important factor underlying HD progression. Metabotropic glutamate receptors (mGluR1 and mGluR5) have a very controversial role in neuronal cell death and it is not clear whether mGluR1/5 activation either protects or exacerbates neuronal death. Thus, understanding how mutant htt protein affects glutamatergic receptor signaling will be essential to further establish a role for glutamate receptors in HD and develop therapeutic strategies to treat HD.

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Molecular Targets and Therapeutic Strategies in Huntingtons Disease

Cited by 20 publications

References 283 publications

Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q

Huntington’s Disease and Group I Metabotropic Glutamate Receptors

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