Subcellular Clearance and Accumulation of Huntington Disease Protein: A Mini-Review

ABSTRACT Polyglutamine expansion causes Huntington disease (HD) and at least seven other neurodegenerative diseases. In HD, N-terminal fragments of huntingtin with an expanded glutamine tract are able to aggregate and accumulate in the nucleus. Although intranuclear huntingtin affects the expression of numerous genes, the mechanism of this nuclear effect is unknown. Here we report that huntingtin interacts with Sp1, a transcription factor that binds to GC-rich elements in certain promoters and activates transcription of the corresponding genes. In vitro binding and immunoprecipitation assays show that polyglutamine expansion enhances the interaction of N-terminal huntingtin with Sp1. In HD transgenic mice (R6/2) that express N-terminal-mutant huntingtin, Sp1 binds to the soluble form of mutant huntingtin but not to aggregated huntingtin. Mutant huntingtin inhibits the binding of nuclear Sp1 to the promoter of nerve growth factor receptor and suppresses its transcriptional activity in cultured cells. Overexpression of Sp1 reduces the cellular toxicity and neuritic extension defects caused by intranuclear mutant huntingtin. These findings suggest that the soluble form of mutant huntingtin in the nucleus may cause cellular dysfunction by binding to Sp1 and thus reducing the expression of Sp1-regulated genes.

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Consumo e dietas “low carb high fat high protein” suas implicações metabólicas, clínicas e nutricionais: uma revisão integrativa

Research Society and Development ◽

10.33448/rsd-v10i16.23575 ◽

2021 ◽

Vol 10 (16) ◽

pp. e282101623575

Author(s):

Saulo Leite de Paula ◽

Maria Rosimar Teixeira Matos ◽

Yanna Cavalcante Martins ◽

Noênia Alves de Araújo ◽

Francisco Sydney Henrique da Silva ◽

...

Keyword(s):

Cardiovascular Disease ◽

Protein A ◽

High Protein ◽

Dietary Carbohydrates ◽

High Fat ◽

Carbohydrate Diet ◽

Pubmed Central ◽

Low Carbohydrate Diet ◽

Low Carbohydrate ◽

Disease Protein

O consumo da dieta da “moda”ow Carb High fat High Protein’ (LCHFHP) está cada vez mais frequente na atualidade por ocasionar erda de peso mais rápida e consequente melhoria na qualidade de vida. A presente revisão integrativa visa identificar as implicações metabólicas, clínicas e nutricionais relacionadas ao consumo de dietas Low Carb High fat High Protein. A pesquisa bibliográfica foi realizada através de buscas nas bases de dados eletrônicas Pubmed Central e Elsevier, no período de 2006 a 2018, com a utilização dos seguintes descritores: “carbohydrate; dietary carbohydrates; diet, low carbohydrate; diet, carbohydrate-restricted; ketosis; diabetes; motor active; obesity; cardiovascular disease; protein; physical activite.” Inicialmente foram encontrados 68.219 artigos. Desses, 40 foram pré-selecionados cumprindo critérios de inclusão. Porém, dentre estes 40, 28 estavam dentro do perfil do estudo. A maioria dos estudos embora demonstrando efeitos positivos com o consumo de dieta LCHFHP, ao curto prazo, quanto à perda de peso, redução no percentual de gordura corporal, melhora da sensibilidade à insulina e no controle glicêmico e redução na utilização de medicações, mostraram que nem sempre esses efeitos foram atribuídos à redução de carboidratos na dieta. Além desses benefícios não terem sido evidenciados ao longo prazo, observou-se aumento nos níveis séricos dos biomarcadores inflamatórios, da extensão da aterosclerose e na morbidade e mortalidade cardiovascular. Realizou-se de mais estudos, principalmente ao longo prazo e com amostragem maior, no sentido de melhor averiguar os benefícios ou riscos decorrentes do consumo dessas dietas, bem como mecanismo de ação, principalmente diante das doenças crônicas não transmissíveis.

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The Huntington disease protein accelerates breast tumour development and metastasis through ErbB2/HER2 signalling

EMBO Molecular Medicine ◽

10.1002/emmm.201201546 ◽

2013 ◽

Vol 5 (2) ◽

pp. 309-325 ◽

Cited By ~ 21

Author(s):

Cristovão Moreira Sousa ◽

John Russel McGuire ◽

Morgane Sonia Thion ◽

David Gentien ◽

Pierre de la Grange ◽

...

Keyword(s):

Huntington Disease ◽

Breast Tumour ◽

Tumour Development ◽

Disease Protein

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The identification of a functional nuclear localization signal in the Huntington disease protein

Molecular Brain Research ◽

10.1016/0169-328x(95)00124-b ◽

1995 ◽

Vol 33 (1) ◽

pp. 165-173 ◽

Cited By ~ 22

Author(s):

Denise A. Bessert ◽

Kristin L. Gutridge ◽

Joan C. Dunbar ◽

Leon R. Carlock

Keyword(s):

Nuclear Localization ◽

Huntington Disease ◽

Nuclear Localization Signal ◽

Disease Protein ◽

Localization Signal ◽

Functional Nuclear Localization Signal

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Rhes travels from cell to cell and transports Huntington disease protein via TNT-like protrusion

The Journal of Cell Biology ◽

10.1083/jcb.201807068 ◽

2019 ◽

Vol 218 (6) ◽

pp. 1972-1993 ◽

Cited By ~ 13

Author(s):

Manish Sharma ◽

Srinivasa Subramaniam

Keyword(s):

Huntington Disease ◽

Live Cell Imaging ◽

Cell Imaging ◽

Mutant Huntingtin ◽

Tunneling Nanotubes ◽

Neighboring Cell ◽

Disease Protein ◽

Electron Microscopy Analysis ◽

Microscopy Analysis ◽

Cell Cell

Tunneling nanotubes (TNT) are thin, membranous, tunnel-like cell-to-cell connections, but the mechanisms underlying their biogenesis or functional role remains obscure. Here, we report, Rhes, a brain-enriched GTPase/SUMO E3-like protein, induces the biogenesis of TNT-like cellular protrusions, “Rhes tunnels,” through which Rhes moves from cell to cell and transports Huntington disease (HD) protein, the poly-Q expanded mutant Huntingtin (mHTT). The formation of TNT-like Rhes tunnels requires the Rhes’s serine 33, C-terminal CAAX, and a SUMO E3-like domain. Electron microscopy analysis revealed that TNT-like Rhes tunnels appear continuous, cell–cell connections, and <200 nm in diameter. Live-cell imaging shows that Rhes tunnels establish contact with the neighboring cell and deliver Rhes-positive cargoes, which travel across the plasma membrane of the neighboring cell before entering it. The Rhes tunnels carry Rab5a/Lyso 20-positive vesicles and transport mHTT, but not normal HTT, mTOR, or wtTau proteins. SUMOylation-defective mHTT, Rhes C263S (cannot SUMOylate mHTT), or CRISPR/Cas9-mediated depletion of three isoforms of SUMO diminishes Rhes-mediated mHTT transport. Thus, Rhes promotes the biogenesis of TNT-like cellular protrusions and facilitates the cell–cell transport of mHTT involving SUMO-mediated mechanisms.

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