Brain‐derived neurotrophic factor over‐expression in the forebrain ameliorates Huntington’s disease phenotypes in mice

Gharami, Kusumika; Xie, Yong; An, Juan Ji; Tonegawa, Susumu; Xu, Baoji

doi:10.1111/j.1471-4159.2007.05137.x

Cited by 163 publications

(161 citation statements)

References 36 publications

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“…45,46 Furthermore, transgenic mice overexpressing BDNF in the cerebral cortex, when cross-mated with R6/1 Conditional release of BDNF in Huntington's disease A Giralt et al mice, improve several morphological and behavioral symptoms. 15 As per these data, the development of a putative neuroprotective therapy based on BDNF could be a successful treatment strategy for the disease. 20,21 Several methods have been tested to deliver neurotrophic factors in the central nervous system.…”

Section: Discussionmentioning

confidence: 98%

“…5 Moreover, upregulation of BDNF in different models of HD improves the disease symptomatology. [14][15][16][17] BDNF can also be relevant in the regulation of cognitive alterations observed in HD. 18,19 Thus, due to its prosurvival effects in striatal and cortical neuropathology, BDNF is the main candidate for neuroprotective therapies 20,21 as it has been tested after intrastriatal administration of quinolinate (QUIN), an N-methyl-Daspartic acid receptor agonist used as an acute model of HD 22 , and in transgenic mouse models.…”

Section: Introductionmentioning

confidence: 99%

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BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

et al. 2010

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Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

et al. 2010

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“…Regulation of transcription by BDNF requires signal transduction systems altered in HD (e.g., phosphatidylinositol-3-kinase and cdk5) [43,178]. Increased BDNF, either by intraventricular injection or prenatal transgenic overexpression, ameliorates the severity of the phenotype in R6 and YAC128 mice, whereas crossing with BDNF heterozygote-null mice exacerbates the phenotype [62,63,179].…”

Section: Bdnf Deficitmentioning

confidence: 99%

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Ehrlich

2012

Neurotherapeutics

120

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Huntington's disease is an autosomal dominant disorder caused by a mutation in the gene encoding the protein huntingtin on chromosome 4. The mutation is an expanded CAG repeat in the first exon, encoding a polyglutamine tract. If the polyglutamine tract is >40, penetrance is 100% and death is inevitable. Despite the widespread expression of huntingtin, HD has long been considered primarily as a disease of the striatum. It is characterized by selective vulnerability with dysfunction followed by death of the medium size spiny neuron. Considerable effort is being expended to determine whether striatal damage is cell-autonomous, non-cell-autonomous, requiring cell-cell and region to region communication, or both. We review data supporting both mechanisms. We also attempt to organize the data into common mechanisms that may arise outside the medium, spiny neuron, but ultimately have their greatest impact in the striatum. characterized by selective, or perhaps better described as differential [2], vulnerability with degeneration and death of the medium spiny neuron (MSN). The Gamma-aminobutyric acid (GABA)ergic MSN represents 95% of striatal neurons. They are all output neurons, with extensive intra-striatal connections with other MSNs and striatal interneurons. For the last two decades, increased attention has been paid to the pathology in the cortex (particularly in layers V and VI [3]), which contains the corticostriatal projection neurons.Prior to identification of the HTT gene, the huntingtin protein, and the nature of its mutation, it was assumed that selective neuronal vulnerability in HD would be conferred by the expression pattern of the mutated protein (polyQ-htt). As it is now apparent, htt is expressed throughout the nervous system and periphery, without a preference for, or higher level in, MSNs or cortical projection neurons [4].In the absence of enriched expression of a mutated protein, neuronal subtype vulnerability was assumed to arise from unique protein interactions. For example, in the study of another polyQ disease, spinocerebellar ataxia 7, the interaction between ataxin-7 and the homeobox protein CRX in the retina was reported to specifically lead to pathology [5]. In a followup study, the specific role of CRX was not confirmed [6]. To complicate matters further, the same group recently demonstrated that the interactions between a mutant polyQ protein, Ataxin-1, and 14-3-3epsilon differentially affects disease state in cerebellum and brainstem, both of which are vulnerable regions [7]. The regional distribution of the described huntingtin interacting proteins by and large does not explain MSN vulnerability [8][9][10]. One exception is the htt interacting protein RASD2/Rhes (Ras homologue enriched in striatum), which is striatal-specific. It is a small G-protein that mediates sumoylation of polyQ-htt, and thereby its neurotoxicity.

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“…In animal models of HD, cortical BDNF expression is reduced (29,30). Moreover, downregulating BDNF in striatum in mice worsens the HD phenotype, whereas elevating BDNF expression in the forebrain alleviates the HD phenotype (31)(32)(33)(34). Studies demonstrating a role for Htt in axonal transport of BDNF strengthen this argument by providing a mechanism by which BDNF delivery to the striatum might be impaired in HD (35), but this point is somewhat controversial (36).…”

Section: Hd Pathogenesis Is Rooted In Network Dysfunctionmentioning

confidence: 99%

Brain networks in Huntington disease

Eidelberg¹,

Surmeier²

2011

J. Clin. Invest.

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Recent studies have focused on understanding the neural mechanisms underlying the emergence of clinical signs and symptoms in early stage Huntington disease (HD). Although cell-based assays have focused on cell autonomous effects of mutant huntingtin, animal HD models have revealed alterations in the function of neuronal networks, particularly those linking the cerebral cortex and striatum. These findings are complemented by metabolic imaging studies of disease progression in premanifest subjects. Quantifying metabolic progression at the systems level may identify network biomarkers to aid in the objective assessment of new disease-modifying therapies and identify new regions that merit mechanistic study in HD models. Neuropathology in Huntington diseaseHuntington disease (HD) is caused by expansion of a CAG repeat in the huntingtin (Htt) gene. Expansion of the repeat length beyond 35 CAGs significantly elevates disease risk (1). The Htt gene is ubiquitously expressed in the brain with relative enrichment in cortical pyramidal neurons projecting to the striatum but relatively low levels in striatal projection neurons (2, 3).Although there are clear effects in the cerebral cortex and hippocampus, the most pronounced neuropathology in HD is found in the striatum (4, 5). The striatum is a key component of the basal ganglia, an interconnected set of subcortical nuclei involved in the regulation of how to act (and not act) in particular contexts (6). The striatum is composed primarily of GABAergic projection neurons with dendrites that are heavily studded with spines. These spiny projection neurons (SPNs) can be subdivided into two major classes on the basis of their axonal projection, dendritic size, and physiology as well as their expression of dopamine receptors and releasable peptides (7,8). SPNs that project to the external segment of the globus pallidus (GPe) form what is called the indirect SPN (iSPN) pathway because they indirectly control the nuclei that interface between the basal ganglia and the rest of the brain. SPNs that project to the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata form the direct SPN (dSPN) pathway. iSPNs are smaller and more excitable than dSPNs (Figure 1 and ref. 9); this difference is very likely to reflect a tonic negative modulation of iSPNs by dopamine acting at D 2 receptors. In contrast, dSPNs are positively modulated by D 1 receptors that appear to only be activated by transient elevations in dopamine release produced by bursts of action potentials in dopaminergic neurons (10).iSPNs and dSPNs are generally thought to play complementary roles in movement control and action selection. Both SPN populations have a rich, highly convergent synaptic connectivity with glutamatergic neurons distributed throughout much of the cerebral cortex (11). Both populations also have rich connectivity with glutamatergic neurons in the thalamus (12). A broad array of experimental evidence supports the proposition that iSPNs help to suppress cortical selection of...

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Brain‐derived neurotrophic factor over‐expression in the forebrain ameliorates Huntington’s disease phenotypes in mice

Cited by 163 publications

References 36 publications

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease

Brain networks in Huntington disease

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