Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival

Burrus, Caley; McKinstry, Spencer U.; Kim, Namsoo; Ozlu, M. Ilcim; Santoki, Aditya V.; Fang, Fengqin; Ma, Annie; Karadeniz, Yonca B.; Worthington, Atesh; Dragatsis, Ioannis; Zeitlin, Scott; Yin, Henry H.; Eroğlu, Çağla

doi:10.1016/j.celrep.2019.12.069

Cited by 38 publications

(34 citation statements)

References 73 publications

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“…Third, in mice with a specific deletion of Htt in Gsx2 lineages (lineage described § II.1 and figure 1B), similar striatal neurodegeneration and motor deficits are observed (Mehler et al, 2019). These latter findings have also been confirmed by a recent study in which a specific deletion of the protein in SPNs was performed (Burrus et al, 2020). The deletion of Htt in iSPNs leads to a dramatic reduction of GABAergic synapses in the GPe, associated with an hyperactivity, in 2 month-old mice.…”

Section: ) Huntingtin Is Crucial For the Cytoarchitectural Organizatsupporting

confidence: 65%

“…These results therefore suggest that Htt is required for the maintenance of basal ganglia circuit integrity. Moreover, this specific deletion of Htt induces HD-like alterations in adulthood, evidenced by SPN loss, motor alterations, and reactive gliosis observed in 10 month-old mice (Burrus et al, 2020).…”

Section: ) Huntingtin Is Crucial For the Cytoarchitectural Organizatmentioning

confidence: 92%

“…The various studies discussed in this review highlight the complexity of the striatum's normal development as well as the deleterious effects of a loss of wild-type Htt function or Htt mutation on striatal development and HD pathogenesis (Burrus et al, 2020;Lopes et al, 2016). Indeed, strong alterations in striatal cytoarchitectural and corticostriatal connectivity are observed when Htt expression is decreased.…”

Section: V-concluding Remarks / Future Directionsmentioning

confidence: 99%

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Striatal Circuit Development and Its Alterations in Huntington’s Disease

Lebouc¹,

Richard²,

Garret³

et al. 2020

Preprint

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Huntington's disease (HD) is an inherited neurodegenerative disorder that usually starts during midlife with progressive alterations of motor and cognitive functions. The disease is caused by a CAG repeat expansion within the huntingtin gene leading to severe striatal neurodegeneration. Recent studies conducted on pre-HD children highlight early striatal developmental alterations starting as soon as 6 years old, the earliest age assessed. These findings, in line with data from mouse models of HD, raise the question of when during development do the first disease-related striatal alterations emerge or whether they contribute to the later appearance of the neurodegenerative features of the disease. In this review we will describe the different stages of striatal network development and then discuss recent evidence for its alterations in rodent models of the disease. We argue that a better understanding of the striatum’s development should help in assessing aberrant neurodevelopmental processes linked to the HD mutation.

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Section: ) Huntingtin Is Crucial For the Cytoarchitectural Organizatsupporting

confidence: 65%

Section: ) Huntingtin Is Crucial For the Cytoarchitectural Organizatmentioning

confidence: 92%

Section: V-concluding Remarks / Future Directionsmentioning

confidence: 99%

See 1 more Smart Citation

Striatal Circuit Development and Its Alterations in Huntington’s Disease

Lebouc¹,

Richard²,

Garret³

et al. 2020

Preprint

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“…Mice with deletion of the Htt gene, Hdh, die around embryonic day 8.5-10.5 before the full emergence of the nervous system, indicating a role for this gene in cell survival and neurogenesis [22][23][24][25] . Conditional deletion of Htt in the mouse brain results in a defect in corticostriatal development, as well as induces hyperactivity, acute pancreatitis, and age-dependent neurodegenerative-like phenotype [26][27][28] . These results indicate that normal HTT plays essential role in the organism's developmental and adult brain functions.…”

mentioning

confidence: 99%

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

et al. 2021

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The polyglutamine expansion of huntingtin (mHTT) causes Huntington disease (HD) and neurodegeneration, but the mechanisms remain unclear. Here, we found that mHtt promotes ribosome stalling and suppresses protein synthesis in mouse HD striatal neuronal cells. Depletion of mHtt enhances protein synthesis and increases the speed of ribosomal translocation, while mHtt directly inhibits protein synthesis in vitro. Fmrp, a known regulator of ribosome stalling, is upregulated in HD, but its depletion has no discernible effect on protein synthesis or ribosome stalling in HD cells. We found interactions of ribosomal proteins and translating ribosomes with mHtt. High-resolution global ribosome footprint profiling (Ribo-Seq) and mRNA-Seq indicates a widespread shift in ribosome occupancy toward the 5′ and 3′ end and unique single-codon pauses on selected mRNA targets in HD cells, compared to controls. Thus, mHtt impedes ribosomal translocation during translation elongation, a mechanistic defect that can be exploited for HD therapeutics.

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“…Afterwards, the slices were incubated overnight with neuronal-specific NeuN (1:500, Merck Millipore) and astrocytic-specific Sox9 (refs. 59 , 60 ) (1:200, Cell Signalling) primary antibodies in a buffer containing PBS 1× plus 0.3% Triton X-100, 0.2% bovine serum albumin. Then, brain sections were washed twice in PBS 1x x during 10 min and incubated for 2 h at room temperature in primary antibody buffer with Alexa Fluor 488 donkey anti-mouse IgG or Alexa Fluor 594 donkey anti-rabbit IgG secondary antibodies (1:1500, Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice

et al. 2021

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Temporal dynamics and mechanisms underlying epigenetic changes in Huntington’s disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.

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Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival

Abstract: Highlights d Loss of Htt in striatal neurons recapitulates key features of Huntington's disease d Striatal neurons require Htt for survival during aging d Deletion of Htt from striatal neurons disrupts synaptic connectivity

Cited by 38 publications

References 73 publications

Striatal Circuit Development and Its Alterations in Huntington’s Disease

Striatal Circuit Development and Its Alterations in Huntington’s Disease

Mutant Huntingtin stalls ribosomes and represses protein synthesis in a cellular model of Huntington disease

Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington’s disease mice

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