Autophagy in Huntington disease and huntingtin in autophagy

Martin, Dale D.O.; Ladha, S; Ehrnhoefer, Dagmar E.; Hayden, Michael R.

doi:10.1016/j.tins.2014.09.003

Cited by 291 publications

(258 citation statements)

References 114 publications

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“…9). These results are consistent with the previous reports that huntingtin and TDP-43 are degraded by autophagy (37)(38)(39)(40). However, we could not detect the protective effect of p62 in the A␤ flies and the Tau flies.…”

Section: Discussionsupporting

confidence: 92%

p62 Plays a Protective Role in the Autophagic Degradation of Polyglutamine Protein Oligomers in Polyglutamine Disease Model Flies

Saitoh

Fujikake

Okamoto

et al. 2015

Journal of Biological Chemistry

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Background: Oligomers of pathogenic proteins are implicated in the pathomechanisms of neurodegenerative diseases. Results: Depletion of p62 delays the degradation of polyglutamine protein oligomers via autophagy and exacerbates neurodegeneration in polyglutamine disease model flies. Conclusion: p62 plays a protective role via autophagic degradation of polyglutamine protein oligomers. Significance: p62 should be a therapeutic target for the polyglutamine diseases.

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Section: Discussionsupporting

confidence: 92%

p62 Plays a Protective Role in the Autophagic Degradation of Polyglutamine Protein Oligomers in Polyglutamine Disease Model Flies

Saitoh

Fujikake

Okamoto

et al. 2015

Journal of Biological Chemistry

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“…Возможно, это связано с тем, что не только наличие мутантного HTT может приводить к гибели клеток, но также недостаток HTT дикого типа значительно сказывается на их выживаемости. HTT вы-полняет важную роль в регуляции аутофагии: он участвует в формировании и транспортировке аутофагосом внутри клеток (Martin et al, 2015). Таким образом, в условиях от-сутствия или нехватки нормального белка дополнительное ингибирование другого пути утилизации отработавших белков -протеолиза -является критичным для жизне-способности клеток.…”

Section: Cell-based Models Of Diseases Vavilov Journal Of Genetics Anunclassified

Huntington’s disease modeling on HEK293 cell line

Sharipova¹,

Malankhanova²,

Malakhova³

2017

Vestn. VOGiS

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Huntington's disease is a hereditary neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the first exon of HTT gene. The mutant HTT protein has an elongated polyglutamine tract and forms aggregates in the nuclei and cytoplasm of the striatal neurons. The pathological processes occurring in the medium spiny neurons of Huntington's disease patients lead to neurodegeneration and consequently to the death. The molecular mechanisms of the pathology development are difficult to study due to the limited material availability and late onset of the manifestation. Therefore, one of the important tasks is generation of an in vitro model system of Huntington's disease based on human cell cultures. The new genome editing approaches, such as CRISPR/Cas9, allow us to generate isogenic cell lines that can be useful for drug screening and studying mechanisms of molecular and cellular events triggered by certain mutation on an equal genetic background. Here, we investigated the viability and proliferative rate of several mutant HEK293 cell clones with mutations in the first exon of HTT gene. The mutant clones were obtained earlier using CRISPR/Cas9 genome editing technology. We showed that mutant cells partially reproduce the pathological phenotype, that is, they have reduced proliferation activity, an increased level of apoptosis and high sensitivity to treatment with 5μM MG132 proteasome inhibitor compared to the original HEK293 Phoenix cell line. Our results indicate that the mutation in the first exon of HTT gene affects not only neurons, but also other types of cells, and HEK293 cell clones bearing the mutation can serve as in vitro model for studying some mechanisms of HTT functioning.Key words: Huntington's disease; cell models; genome editing.Болезнь Хантингтона -наследственное нейродегенеративное заболевание человека, которое вызвано мутацией в гене НТТ. Мутантный белок НТТ имеет удлиненный полиглутаминовый тракт и образует агрегаты в ядре и цитоплазме средних шипиковых ней-ронов стриатума, приводя их к гибели. Механизмы развития за-болевания до конца не изучены, ввиду ограниченной доступности биоматериала и позднего проявления болезни. Именно поэтому одной из актуальных задач является создание модельных систем болезни Хантингтона на основе культивируемых клеток челове-ка. Сочетание клеточных технологий и системы редактирования генома CRISPR/ Cas9 позволит изучать молекулярные и клеточные механизмы развития патологии. Ранее в лаборатории эпигенетики развития Института цитологии и генетики СО РАН была разработа-на методика внесения мутации, вызывающей болезнь Хантингтона, в геном клеток человека и получены мутантные клоны клеток линии HEK293, моделирующие болезнь Хантингтона. В данной работе мы показали, что мутантные клетки частично воспроиз-водят патологический фенотип, а именно: обладают сни женной пролиферативной активностью, повышенным уровнем апоптоза и высокой чувствительностью к ингибитору протеасом (MG132). Полученные результаты свидетельствуют о том, что мутация, вы-зывающая болезнь Хантин...

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“…48,49 The three main stages of macroautophagy are autophagosome formation, maturation and fusion with lysosomes. 39 During the first stage, autophagosome formation, an isolation membrane forms to surround proteins or whole organelles.…”

Section: Autophagic Dysfunction In Hdmentioning

confidence: 99%

“…39 During the first stage, autophagosome formation, an isolation membrane forms to surround proteins or whole organelles. 49 Fifteen autophagy-related (ATG) proteins have key roles in formation of the autophagosome.…”

Section: Autophagic Dysfunction In Hdmentioning

confidence: 99%

Primary cilia and autophagic dysfunction in Huntington’s disease

2015

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Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by a single-gene mutation: a CAG expansion in the huntingtin (HTT) gene that results in production of a mutated protein, mutant HTT, with a polyglutamine tail (polyQ-HTT). Although the molecular pathways of polyQ-HTT toxicity are not fully understood, because protein misfolding and aggregation are central features of HD, it has long been suspected that cellular housekeeping processes such as autophagy might be important to disease pathology. Indeed, multiple lines of research have identified abnormal autophagy in HD, characterized generally by increased autophagic induction and inefficient clearance of substrates. To date, the origin of autophagic dysfunction in HD remains unclear and the search for actors involved continues. To that end, recent studies have suggested a bidirectional relationship between autophagy and primary cilia, signaling organelles of most mammalian cells. Interestingly, primary cilia structure is defective in HD, suggesting a potential link between autophagic dysfunction, primary cilia and HD pathogenesis. In addition, because polyQ-HTT also accumulates in primary cilia, the possibility exists that primary cilia might play additional roles in HD: perhaps by disrupting signaling pathways or acting as a reservoir for secretion and propagation of toxic, misfolded polyQ-HTT fragments. Here, we review recent research suggesting potential links between autophagy, primary cilia and HD and speculate on possible pathogenic mechanisms and future directions for the field.

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Autophagy in Huntington disease and huntingtin in autophagy

Cited by 291 publications

References 114 publications

p62 Plays a Protective Role in the Autophagic Degradation of Polyglutamine Protein Oligomers in Polyglutamine Disease Model Flies

p62 Plays a Protective Role in the Autophagic Degradation of Polyglutamine Protein Oligomers in Polyglutamine Disease Model Flies

Huntington’s disease modeling on HEK293 cell line

Primary cilia and autophagic dysfunction in Huntington’s disease

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