ArticleHuman molecular genetics2015
Disruption of the nuclear membrane by perinuclear inclusions of mutant huntingtin causes cell-cycle re-entry and striatal cell death in mouse and cell models of Huntington's disease.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 112 citations in OpenAlex.
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- Interventionally targeting somatic CAG expansions can be a rapid disease-modifying therapeutic avenue: Preclinical evidence.bioRxiv : the preprint server for biology · 2025Article
- Nuclear pore dysfunction and disease: a complex opportunity.Nucleus (Austin, Tex.) · 2024Review
- Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair.The Journal of cell biology · 2024Article
- Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination.Communications biology · 2024Article
- Endosome mediated nucleocytoplasmic trafficking and endomembrane allocation is crucial to polyglutamine toxicity.Cell biology and toxicology · 2024Article
- Differential Effects of Post-translational Modifications on the Membrane Interaction of Huntingtin Protein.ACS chemical neuroscience · 2024Article
- The N17 domain of huntingtin as a multifaceted player in Huntington's disease.Frontiers in molecular biosciences · 2024Review
- Charge within Nt17 peptides modulates huntingtin aggregation and initial lipid binding events.Biophysical chemistry · 2023Article
- Nuclear envelope budding and its cellular functions.Nucleus (Austin, Tex.) · 2023Article
- Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2.EMBO molecular medicine · 2023Article
- Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration.FEBS letters · 2023Review
- Oxidation Promotes Distinct Huntingtin Aggregates in the Presence and Absence of Membranes.Biochemistry · 2022Article
- Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors.Biology · 2022Review
- Spermatozoan Metabolism as a Non-Traditional Model for the Study of Huntington's Disease.International journal of molecular sciences · 2022Review
- Identification of cyclin D1 as a major modulator of 3-nitropropionic acid-induced striatal neurodegeneration.Neurobiology of disease · 2022Article
- Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties.Nature communications · 2021Article
- Macromolecular crowding in solution alters huntingtin interaction and aggregation at interfaces.Colloids and surfaces. B, Biointerfaces · 2021Article
- Mitochondrial membranes modify mutant huntingtin aggregation.Biochimica et biophysica acta. Biomembranes · 2021Article
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Accumulation of N-terminal fragments of mutant huntingtin (mHTT) in the cytoplasm, nuclei and axons of neurons is a hallmark of Huntington's disease (HD), although how these fragments negatively impact neurons remains unclear. We followed the distribution of mHTT in the striata of transgenic R6/2-J2 HD mice as their motor function declined. The fraction of cells with diffuse, perinuclear or intranuclear mHTT changed in parallel with decreasing motor function. In transgenic mice, medium spiny neurons (MSNs) that exhibited perinuclear inclusions expressed cell-cycle markers typically not seen in the striata of normal mice, and these cells are preferentially lost as disease progresses. Electron microscopy reveals that perinuclear inclusions disrupt the nuclear envelope. The progression of perinuclear inclusions being accompanied by cell-cycle activation and culminating in cell death was also observed in 1° cortical neurons. These observations provide a strong correlation between the subcellular location of mHTT, disruption of the nucleus, re-entry into the cell-cycle and eventual neuronal death. They also highlight the fact that the subcellular distribution of mHTT is highly dynamic such that the distribution of mHTT observed depends greatly on the stage of the disease being examined.
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