Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease

Wang, Nan; Gray, Michelle; Lu, Xiao‐Hong; Cantle, Jeffrey P.; Holley, Sandra M.; Greiner, Erin R.; Gu, Xiaofeng; Shirasaki, Dyna I.; Cepeda, Carlos; Li, Yuqing; Dong, Hong‐Wei; Levine, Michael S.; Yang, Xiangdong

doi:10.1038/nm.3514

Cited by 181 publications

(165 citation statements)

References 37 publications

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“…Moreover, a recent study using BACHD mice showed that disease phenotypes can only be fully rescued when mutant Htt is deleted from both the cortex and striatum, demonstrating the distinct yet interacting roles of cortical and striatal mutant Htt in HD (Wang et al, 2014). We found that the striatal connections in Htt cortical cKO remain stronger and numerous in 5 week mice even though intracortical connectivity of layer 5 neurons in these mice is diminishing.…”

Section: Htt Is Required To Mold the Circuitry Of The Cortex Striatumentioning

confidence: 52%

Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits

McKinstry

Karadeniz

Worthington

et al. 2014

Journal of Neuroscience

131

138

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Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a poly-glutamine (poly-QTo determine whether the disease-causing poly-Q mutation in Htt affects synapse development, we next investigated the synaptic connectivity in a full-length knock-in mouse model of HD, the zQ175 mouse. Similar to the cortical conditional knock-outs, we found excessive excitatory synapse formation and maturation in the cortices of P21 zQ175, which was lost by 5 weeks. Together, our findings reveal that cortical Htt is required for the correct establishment of cortical and striatal excitatory circuits, and this function of Htt is lost when the mutant Htt is present.

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Section: Htt Is Required To Mold the Circuitry Of The Cortex Striatumentioning

confidence: 52%

Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits

McKinstry

Karadeniz

Worthington

et al. 2014

Journal of Neuroscience

131

138

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“…We showed that individual CCT subunits reduced mHTTQ97 in PC12 cells and that CCT3 and ApiCCT1 reduced mHTT in BACHD neurons. Targeting the levels of mHTT to reverse salient features of HD pathogenesis has been suggested by others (59)(60)(61) and has been supported by elegant studies demonstrating that reducing mHTT expression in BACHD neurons improves HD-relevant phenotypes (6,55). Further work will be needed to define the mechanism(s) by which mHTT induces HD pathogenesis and what role is played by deficits in BDNF transport and signaling.…”

Section: Impaired Lysosome Transport In Bachd Cortical Neurons Wasmentioning

confidence: 95%

“…It has been shown that mHTT has an impact on axonal trafficking and signaling, synaptic function, gene expression, mitochondrial function, calcium homeostasis, and proteostasis (4,5). Thus, mHTT plays a central role in HD pathogenesis, an assertion fully supported by recent studies in the BACHD model of HD (6).…”

mentioning

confidence: 85%

TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease

Zhao

Chen

Han

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

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Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagentmediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons., a genetically defined progressive neurodegenerative disorder, is characterized by abnormal involuntary movements, cognitive disability, and psychiatric symptoms (1). The pathogenesis of HD is due to an expanded CAG repeat in the huntingtin (HTT) gene, which encodes the protein Htt. Mutant Htt (mHTT) features an increased number of glutamines (Q > 36) near the N terminus. The striking atrophy and loss of striatal medium-sized spiny neurons (MSNs) in the HD brain are accompanied by atrophy of the cortex (2). The mechanisms by which mHTT induces dysfunction and death of neurons are actively explored (3). It has been shown that mHTT has an impact on axonal trafficking and signaling, synaptic function, gene expression, mitochondrial function, calcium homeostasis, and proteostasis (4, 5). Thus, mHTT plays a central role in HD pathogenesis, an assertion fully supported by recent studies in the BACHD model of HD (6).One productive line of inquiry regarding HD pathogenesis focuses on brain-derived neurotrophic factor (BDNF), which sustains neurons of the corticostriatal circuit (7-10). In the corticostriatal circuit, BDNF is produced in cortical neurons and is transported anterogradely in axons before secretion in striatum. Released BDNF binds to tyrosine receptor kinase B (TrkB) on striatal MSNs, resulting in BDNF-mediated signaling. Because MSNs do not produce BDNF, they are largely dependent on cortical neurons for i...

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“…ACCEPTED MANUSCRIPT 20 whereas reduction of mhtt in both cortical and striatal populations ameliorates all behavioural deficits and the selective brain atrophy [176]. Moreover, abnormal fat cell function has been reported in several mouse models of HD.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Role of metabolism in neurodegenerative disorders

et al. 2016

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Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease

Cited by 181 publications

References 37 publications

Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits

Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits

TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease

Role of metabolism in neurodegenerative disorders

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