Deletion of the Huntingtin Polyglutamine Stretch Enhances Neuronal Autophagy and Longevity in Mice

Zheng, Shaoyong; Clabough, Erin B. D.; Sarkar, Sovan; Futter, Marie; Rubinsztein, David C.; Zeitlin, Scott

doi:10.1371/journal.pgen.1000838

Cited by 146 publications

(118 citation statements)

References 67 publications

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“…S1B), a brain region that shows relatively early lipofuscin accumulation in aging rodents and for which dysfunction is implicated in HD (23,24). Lipofuscin and ubiquitin accumulation is similarly pronounced in striata from CAG140 HD mice (25,26). Although most Htt −/− mutants die before 15 mo of age because of hydrocephalus, in one surviving 2-y-old mutant mouse with milder hydrocephalus, ubiquitin and p62 puncta and lipofuscin accumulation were also prevalent in the striatum, similar to what we observed in 2-y-old 140Q/+ mouse striatum (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Potential function for the Huntingtin protein as a scaffold for selective autophagy

Ochaba

Lukácsovich²,

Csikos

et al. 2014

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

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252

228

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Although dominant gain-of-function triplet repeat expansions in the Huntingtin (HTT) gene are the underlying cause of Huntington disease (HD), understanding the normal functions of nonmutant HTT protein has remained a challenge. We report here findings that suggest that HTT plays a significant role in selective autophagy. Loss of HTT function in Drosophila disrupts starvationinduced autophagy in larvae and conditional knockout of HTT in the mouse CNS causes characteristic cellular hallmarks of disrupted autophagy, including an accumulation of striatal p62/SQSTM1 over time. We observe that specific domains of HTT have structural similarities to yeast Atg proteins that function in selective autophagy, and in particular that the C-terminal domain of HTT shares structural similarity to yeast Atg11, an autophagic scaffold protein. To explore possible functional similarity between HTT and Atg11, we investigated whether the C-terminal domain of HTT interacts with mammalian counterparts of yeast Atg11-interacting proteins. Strikingly, this domain of HTT coimmunoprecipitates with several key Atg11 interactors, including the Atg1/Unc-51-like autophagy activating kinase 1 kinase complex, autophagic receptor proteins, and mammalian Atg8 homologs. Mutation of a phylogenetically conserved WXXL domain in a C-terminal HTT fragment reduces coprecipitation with mammalian Atg8 homolog GABARAPL1, suggesting a direct interaction. Collectively, these data support a possible central role for HTT as an Atg11-like scaffold protein. These findings have relevance to both mechanisms of disease pathogenesis and to therapeutic intervention strategies that reduce levels of both mutant and normal HTT.rodegenerative disorder caused by an expansion of a CAG trinucleotide repeat encoding a polyglutamine (polyQ) tract near the N terminus of the 350-kD Huntingtin protein (HTT) (1). Identifying the normal biological function of the HTT protein is important in the effort to design and implement effective therapeutic interventions for HD, but has proved challenging.In the mouse, loss of HTT leads to lethality during gastrulation at embryonic day 7 (2-4). Conditional inactivation of HTT in the mouse forebrain at postnatal or late embryonic stages causes a progressive neurodegenerative phenotype associated with neuronal degeneration, motor phenotypes, and early mortality (5). Loss of HTT in mouse cells reduces primary cilia formation, and deletion of HTT in ependymal cells leads to alteration of the cilia layer, suggesting a role for HTT in ciliogenesis (6). Mutant HTT expression and HTT knockdown have also been found to impair axonal trafficking of vesicles, mitochondria, and autophagosomes in neurons in vitro and in vivo (7-9). A clear molecular mechanism to relate these findings to the function of the HTT protein, however, has not yet emerged.In contrast to the embryonic lethality observed in the mouse, Drosophila lacking the endogenous Htt gene develop normally. However, adult Drosophila HTT loss-of-function (LOF) flies show an accelerated neurodege...

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Section: Resultsmentioning

confidence: 99%

“…Brains were frozen and subjected to analysis as described in SI Materials and Methods. p62/SQSTM1 was detected by Western analysis in the striatal insoluble pellet fraction and quantitated as previously described (26).…”

Section: Methodsmentioning

confidence: 99%

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Ochaba

Lukácsovich²,

Csikos

et al. 2014

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

Self Cite

252

228

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“…For example, expression of full-length HTT lacking its polyQ (ΔQ-HTT) in a knock-in mouse model of HD increases autophagy markers and longevity. 65 In vitro expression of ΔQ-HTT also increases autophagosome synthesis and ATG5-dependent clearance of HTT aggregates. 65 In addition, a new study reported that WT-HTT serves as an important scaffold protein in multiple types of selective macroautophagy (not including starvation-induced autophagy) in Drosophila and mammalian cells (including mouse embryonic fibroblasts and striatal cells).…”

Section: 51mentioning

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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“…Two htt-interacting proteins, Rab5 and Rhes, are positive regulators of autophagy (73,74), and htt lacking the polyglutamine repeat region induces autophagy and is protective against toxicity of mutant polyglutamine-expanded htt in cells and mice (75), suggesting a more direct role for htt in autophagy.…”

Section: Autophagy In the Pathogenesis Of Neurodegenerative Diseasementioning

confidence: 99%

Autophagy and neurodegeneration

Rubinsztein

2012

Free Radical Biology and Medicine

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Deletion of the Huntingtin Polyglutamine Stretch Enhances Neuronal Autophagy and Longevity in Mice

Cited by 146 publications

References 67 publications

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Potential function for the Huntingtin protein as a scaffold for selective autophagy

Primary cilia and autophagic dysfunction in Huntington’s disease

Autophagy and neurodegeneration

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