Pharmaceutical, cellular and genetic therapies for Huntington's disease

Handley, Olivia; Naji, Jenny J.; Dunnett, Stephen B.; Rosser, Anne Elizabeth

doi:10.1042/cs20050148

Cited by 46 publications

(23 citation statements)

References 149 publications

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“…However, since clinical trials of mechanismbased therapies for HD have been limited by insufficient statistical power and insignificant improvement (Handley et al, 2006), current clinical treatments are symptomatic. The major neurological symptoms associated with HD include disordered voluntary movements: uncoordinated, arrhythmic, and slow fine motor movements; rigidity; and gait disturbances (Harper, 1991).…”

Section: Discussionmentioning

confidence: 99%

Striatal Expression of a Calmodulin Fragment Improved Motor Function, Weight Loss, and Neuropathology in the R6/2 Mouse Model of Huntington's Disease

Dai¹,

Dudek²,

Li³

et al. 2009

J. Neurosci.

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a polyglutamine expansion in the huntingtin protein (htt). Increasing evidence suggests that transglutaminase (TGase) plays a critical role in the pathophysiology of HD possibly by stabilizing monomeric, polymeric and aggregated htt. We previously reported that in HEK293 and SH-SY5Y cells expression of a calmodulin (CaM)-fragment, consisting of amino acids 76-121 of CaM, decreased binding of CaM to mutant htt, TGase-modified htt and cytotoxicity associated with mutant htt and normalized intracellular calcium release. In this study, an adeno-associated virus (AAV) that expresses the CaM-fragment was injected into the striatum of HD transgenic R6/2 mice. The CaM-fragment significantly reduced body weight loss and improved motor function as indicated by improved rotarod performance, longer stride length, lower stride frequency, fewer low mobility bouts and longer travel distance than HD controls. A small but insignificant increase in survival was observed in R6/2 mice with CaM-fragment expression. Immunoprecipitation studies show that expression of the CaM-fragment reduced TGase-modified htt in the striatum of R6/2 mice. The percentage of htt-positive nuclei and the size of intranuclear htt aggregates were reduced by the CaM-fragment without striatal volume changes. The effects of CaM-fragment appear to be selective, as activity of another CaM-dependent enzyme, CaM-dependent kinase II, was not altered. Moreover, inhibition of TGase-modified htt was substrate-specific since overall TGase activity in the striatum was not altered by treatment with the CaM-fragment. Together, these results suggest that disrupting CaM-htt interaction may provide a new therapeutic strategy for HD.

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Section: Discussionmentioning

confidence: 99%

Striatal Expression of a Calmodulin Fragment Improved Motor Function, Weight Loss, and Neuropathology in the R6/2 Mouse Model of Huntington's Disease

Dai¹,

Dudek²,

Li³

et al. 2009

J. Neurosci.

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“…Chorea Several reviews have summarized the symptomatic treatment of chorea associated with HD [49][50][51][52][53][54][55][56][57][58][59][60][61]. Overall, there is not enough evidence available to guide long-term symptomatic treatment in HD, and double-blind and long-term studies assessing various treatment strategies in HD are needed [55].…”

Section: Pharmacological Treatment Optionsmentioning

confidence: 99%

Treatment of Huntington's Disease

2014

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“…The NMDA receptors are also effective in mediating excitotoxic neuronal injury. For example, neurons expressing high levels of NMDA receptors are lost early in the striatum of individuals affected with neurodegenerative disease, and injection of NMDA receptor agonists into the striatum of rodents or non-human primates recapitulates the pattern of neuronal damage in Huntington's disease (HD) [11] .…”

Section: Ionotropic and Metabotropic Glutamate Receptorsmentioning

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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Pharmaceutical, cellular and genetic therapies for Huntington's disease

Cited by 46 publications

References 149 publications

Striatal Expression of a Calmodulin Fragment Improved Motor Function, Weight Loss, and Neuropathology in the R6/2 Mouse Model of Huntington's Disease

Striatal Expression of a Calmodulin Fragment Improved Motor Function, Weight Loss, and Neuropathology in the R6/2 Mouse Model of Huntington's Disease

Treatment of Huntington's Disease

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

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