Huntington Disease

Vonsattel, Jean Paul; DiFiglia, Marian

doi:10.1097/00005072-199805000-00001

Cited by 1,294 publications

(974 citation statements)

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“…Neuropsychiatry changes are caused by the dysfunction or death of specific neuronal cell types in the brain. GABAergic projections of medium-size spiny neurons (MSNs) of the neostriatum are the most severely affected [61] . Notably, increasing GABA receptor function has been shown to promote neuronal survival after ischemia by depressing the overall excitability of the cell [62,63] .…”

Section: Excitotoxicity In Neurodegenerative Diseasesmentioning

confidence: 99%

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

2009

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A pivotal role for excitotoxicity in neurodegenerative diseases is gaining increasingly more acceptance, but the underlying mechanisms through which it participates in neurodegeneration still need further investigation. Excessive activation of glutamate receptors by excitatory amino acids leads to a number of deleterious consequences, including impairment of calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Recent studies implicate excitotoxicity in a variety of neuropathological conditions, suggesting that neurodegenerative diseases with distinct genetic etiologies may share excitotoxicity as a common pathogenic pathway. Thus, understanding the pathways involved in excitotoxicity is of critical importance for the future clinical treatment of many neurodegenerative diseases. This review discusses the current understanding of excitotoxic mechanisms and how they are involved in the pathogenesis of neurodegenerative diseases.

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Section: Excitotoxicity In Neurodegenerative Diseasesmentioning

confidence: 99%

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

2009

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“…HD is featured by motor, cognitive and psychiatric disturbances, neuronal dysfunction, atrophy of the striatum and other brain regions, and progressive loss of striatal mediumsized spiny neurons (MSNs) and of cortical pyramidal neurons (Vonsattel et al 1998). Several molecular and cellular dysfunctions have been identified (Zuccato et al 2010) and one affected pathway implicates brain cholesterol.…”

Section: Huntington' S Diseasementioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

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“…The length of the poly-Q stretch inversely correlates with the age of onset of symptoms. 2 A repeat length of more than 70 glutamines leads to a juvenile form of the disease and the more commonly occurring poly-Q length of 40-55 typically leads to onset of symptoms at an age of 35-50 years. 2 Most commonly patients die 15-20 years after the onset of the first symptoms, due to complications of immobilization.…”

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confidence: 99%

Mutant huntingtin can paradoxically protect neurons from death

Züchner

Brundin

2007

Cell Death Differ

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Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a mutation in the gene huntingtin and characterized by motor, cognitive and psychiatric symptoms. Huntingtin contains a CAG repeat in exon 1. An expansion of this CAG repeat above 35 results in misfolding of Huntingtin, giving rise to protein aggregates and neuronal cell death. There are several transgenic HD mouse models that reproduce most of the features of the human disorder, for example protein inclusions, some neurodegeneration as well as motor and cognitive symptoms. At the same time, a subgroup of the HD transgenic mouse models exhibit dramatically reduced susceptibility to excitotoxicity. The mechanism behind this is unknown. Here, we review the literature regarding this phenomenon, attempt to explain what protein domains are crucial for this phenomenon and point toward a putative mechanism. We suggest, that the C-terminal domain of exon 1 Huntingtin, namely the proline rich domain, is responsible for mediating a neuroprotective effect against excitotoxicity. Furthermore, we point out the possible importance of this mechanism for future therapies in neurological disorders that have been suggested to be associated with excitotoxicity, for example Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

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Huntington Disease

Cited by 1,294 publications

References 0 publications

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

Nanoparticle transport across the blood brain barrier

Mutant huntingtin can paradoxically protect neurons from death

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