Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease

Zuccato, Chiara; Ciammola, Andrea; Rigamonti, Dorotea; Leavitt, Blair R.; Goffredo, Donato; Conti, Luciano; MacDonald, Marcy E.; Friedlander, Robert M.; Silani, Vincenzo; Hayden, Michael R.; Timmusk, Tõnis; Sipione, Simonetta; Cattaneo, Elena

doi:10.1126/science.1059581

Cited by 1,170 publications

(927 citation statements)

References 36 publications

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“…Several studies have linked BDNF to the etiology of HD, which is characterized by impaired BDNF expression and axonal transports. Notably, BDNF expression can be regulated by wild-type huntingtin at both transcriptional and post-transcriptional levels, suggesting that its production and availability might be limited in the HD brain [110,111]. BDNF is normally present at high levels in the caudate and putamen, in which it is released from corticostriatal afferents [112].…”

Section: Bdnf Induces a Neuronal Addition To The Adult Striatummentioning

confidence: 99%

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Benraiss

Goldman

2011

Neurotherapeutics

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Section: Bdnf Induces a Neuronal Addition To The Adult Striatummentioning

confidence: 99%

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Benraiss

Goldman

2011

Neurotherapeutics

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“…Huntingtin is a widely expressed, predominantly cytoplasmic, protein of unknown function found heterogeneously in neurons throughout the brain and widely in the body. 48 -52 In HD, both normal and mutant alleles are expressed, and both gain of function alterations (in which mutant huntingtin is toxic) and loss of function alterations [53][54][55] (in which suppression of normal huntingtin functions might also be toxic) have been identified.…”

Section: Candidate Targets For Neuroprotectionmentioning

confidence: 99%

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

Hersch

Rosas

2008

Neurotherapeutics

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Summary:The ultimate goal for Huntington's disease (HD) therapeutics is to develop disease-modifying neuroprotective therapies that can delay or prevent illness in those who are at genetic risk and can slow progression in those who are affected clinically. Neuroprotection is the preservation of neuronal structure, function, and viability, and neuroprotective therapy is thus targeted at the underlying pathology of HD, rather than at its specific symptoms. Preclinical target discovery research in HD is identifying numerous distinct targets, along with options for modulating them, with some proceeding into large-scale efficacy studies in early symptomatic HD subjects. The first pilot studies of neuroprotective compounds in premanifest HD are also soon to begin. This review discusses the opportunities for neuroprotection in HD, clinical methodology in premanifest and manifest HD, the clinical assessment of neuroprotection, molecular targets and therapeutic leads, and the current state of clinical development.

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“…Mutant HTT loses this beneficial activity, resulting in decreased production of cortical BDNF. 95 Thus, delivery of the BDNF gene has the potential to provide therapeutic efficacy in HD.…”

Section: Delivery Of Neurotrophic Factor Genes Into the Striatum In Hmentioning

confidence: 99%

Advances in Gene Therapy for Movement Disorders

Mochizuki

Yasuda

Mouradian³

2008

Neurotherapeutics

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Summary:After nearly 20 years of preclinical experimentation with various gene delivery approaches in animal models of Parkinson's disease (PD), clinical trials are finally underway. The risk/benefit ratio for these procedures is now generally considered acceptable under approved protocols. The current vehicle for gene delivery to the human brain is recombinant adeno-associated viral vector, which is nonpathogenic and non-self-amplifying. Candidate genes tested in PD patients encode 1) glutamic acid decarboxylase, which is injected into the subthalamic nucleus to catalyze biosynthesis of the inhibitory neurotransmitter ␥-aminobutyric acid and so essentially mimic deep brain stimulation of this nucleus; 2) aromatic Lamino acid decarboxylase, which converts L-dopa to dopamine; and 3) neurturin, a member of the glial cell line-derived neurotrophic factor family. Unraveling the genetic underpinnings of PD could allow gene therapy to go beyond modulating neurotransmission or providing trophic effects to dopaminergic neurons by delivering a specific missing or defective gene. For example, the parkin gene (PARK2) is linked to recessively inherited PD due to loss of function mutations; it prevents ␣-synuclein-induced degeneration of nigral dopaminergic neurons in rats and nonhuman primates. On the other hand, for dominantly inherited Huntington's disease (HD), in which an expanded polyglutamine tract imparts to the protein huntingtin a toxic gain of function, repressing expression of the mutant allele in the striatum using RNA interference technology mitigates pathology and delays the phenotype in a mouse model. Here we review the current state of preclinical and clinical gene therapy studies conducted in PD and HD.

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Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease

Cited by 1,170 publications

References 36 publications

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

Neuroprotection for Huntington’s Disease: Ready, Set, Slow

Advances in Gene Therapy for Movement Disorders

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