Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice

Wheeler, Vanessa C.; White, Jacqueline K.; Gutekunst, Claire‐Anne; Vrbanac, Vladimir; Weaver, Meredith; Li, Shengbo Eben; Li, Shihua; Yi, Hong; Vonsattel, Jean‐Paul; Gusella, James F.; Hersch, Steven M.; Auerbach, Wojtek; Joyner, Alexandra L.; MacDonald, Marcy E.

doi:10.1093/hmg/9.4.503

Cited by 424 publications

(302 citation statements)

References 37 publications

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“…ABHD12 −/− mice were assessed in a battery of behavioral tests potentially relevant to the symptoms of PHARC disease. Initial behavioral studies were performed with relatively young mice (5-6 mo old), but considering that neurodegenerative phenotypes often only become apparent in aged mice, even for disease models with childhood onset in humans (7)(8)(9)(10), this panel of tests was repeated when mice were 11-12 and 17-18 mo old.…”

Section: Resultsmentioning

confidence: 99%

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

Blankman

Long

Trauger

et al. 2013

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

167

279

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Advances in human genetics are leading to the discovery of new disease-causing mutations at a remarkable rate. Many such mutations, however, occur in genes that encode for proteins of unknown function, which limits our molecular understanding of, and ability to devise treatments for, human disease. Here, we use untargeted metabolomics combined with a genetic mouse model to determine that the poorly characterized serine hydrolase α/β-hydrolase domain-containing (ABHD)12, mutations in which cause the human neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract), is a principal lysophosphatidylserine (LPS) lipase in the mammalian brain. ABHD12 −/− mice display massive increases in a rare set of very long chain LPS lipids that have been previously reported as Toll-like receptor 2 activators. We confirm that recombinant ABHD12 protein exhibits robust LPS lipase activity, which is also substantially reduced in ABHD12 −/− brain tissue. Notably, elevations in brain LPS lipids in ABHD12 −/− mice occur early in life (2-6 mo) and are followed by age-dependent increases in microglial activation and auditory and motor defects that resemble the behavioral phenotypes of human PHARC patients. Taken together, our data provide a molecular model for PHARC, where disruption of ABHD12 causes deregulated LPS metabolism and the accumulation of proinflammatory lipids that promote microglial and neurobehavioral abnormalities.lipidomics | neuroinflammation G enome mapping and sequencing have facilitated determination of the genetic basis for over 3,500 inherited diseases in humans (1), with additional pathogenic mutations still being discovered. For many Mendelian disorders, however, the molecular and cellular mechanisms that link genotype to disease phenotype remain poorly understood. This problem is perhaps most apparent for diseases where the causative mutations occur in genes that encode for proteins with unannotated or poorly characterized functions. Here, we focus on one such disease -the neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract).PHARC [Mendelian Inheritance in Man (MIM) no. 612674; Online Mendelian Inheritance in Man database, http://omim.org] is a rare, autosomal recessive disorder that causes polymodal sensory and motor defects associated with demyelination of sensomotor neurons, retinal dystrophy, and cerebellar atrophy (2). PHARC symptoms are slowly progressive and begin in the childhood or teenage years; heterozygous carriers are unaffected (3). In 2010, PHARC was reported to be caused by homozygous mutations in ABHD12, which codes for the poorly characterized serine hydrolase enzyme α/β-hydrolase domain-containing (ABHD)12 (3). To date, five distinct ABHD12 mutations have been identified in patients with PHARC, all of which are expected to lead to complete loss of ABHD12 expression (3, 4). PHARC, therefore, likely represents a human ABHD12 null model.We demonstrated previously that ABHD12 is a membranebound e...

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Section: Resultsmentioning

confidence: 99%

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

Blankman

Long

Trauger

et al. 2013

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

167

279

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“…So, in human disease, could the aggregation of mutant huntingtin be effectively knocking out normal function by sequestering wildtype huntingtin? This hypothesis is supported by mutant huntingtin knock-in mouse studies and cell culture experiments that show mutant huntingtin recruits wild-type protein into the nucleus and to inclusions (21,22).…”

Section: Loss Of Huntingtin Functionmentioning

confidence: 93%

Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Hatters

2008

IUBMB Life

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SummaryHuntington's disease is one of the several neurodegenerative diseases caused by dominant mutations that expand the number of glutamine codons within an existing poly-glutamine (polyQ) repeat sequence of a gene. An expanded polyQ sequence in the huntingtin gene is known to cause the huntingtin protein to aggregate and form intracellular inclusions as disease progresses. However, the role that polyQ-induced aggregation plays in disease is yet to be fully determined. This review focuses on key questions remaining for how the expanded polyQ sequences affect the aggregation properties of the huntingtin protein and the corresponding effects on cellular machinery. The scope includes the technical challenges that remain for rigorously assessing the effects of aggregation on the cellular machinery.2008 IUBMB IUBMB Life, 60(11): 724-728, 2008

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“…S4). This is not surprising, as binding of mAb2166 antibodies has been shown to be affected by huntingtin conformational changes induced by expansion of the polyQ stretch (43) and/or huntingtin posttranslational modifications (10).…”

Section: Gm1 Triggers Phosphorylation Of Huntingtin At Serine 13 and mentioning

confidence: 96%

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

Pardo

Maglione

Alpaugh

et al. 2012

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

151

143

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Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis.H untington disease (HD) is an inherited neurodegenerative monogenic disorder caused by the expansion of a polyglutamine stretch beyond 36 residues in the amino-terminal domain of huntingtin (Htt), a protein expressed in most tissues and cells. The mutation causes huntingtin to acquire toxic conformation/s and to affect neuronal function and viability. Medium-sized spiny neurons in the corpus striatum are most affected, but neurodegeneration also occurs in the cerebral cortex and, to a minor extent, in other brain areas, resulting in motor and psychiatric symptoms, as well as cognitive decline.The cellular and molecular mechanisms underlying HD pathogenesis are complex. Both loss and gain of function of mutant huntingtin contribute to cause a wide array of neuronal dysfunctions affecting cell signaling, gene transcription, axonal transport, cell and mitochondrial metabolism as well as neurotransmission (1).In recent years, a breakthrough in HD research has been the discovery that posttranslational modifications of mutant Htt are crucial modulators of mutant Htt toxicity (2-4). Phosphorylation at various serine residues prevents cleavage of mutant huntingtin into more toxic fragments, decreases neural cell death in vitro (5-10), and/or restores Htt functions that are compromised by the mutation (8, 11). The most dramatic effects have been described for huntingtin phosphorylation at serine 13 and serine 16. These two amino acid residues are part of the highly conserved amino-terminal "N17" domain of huntingtin, a domain that regulates huntingtin intracellular localization and association to cellular membranes (12, 13), as well as kinetics of mutant huntingtin aggregation (14,15). Phosphomimetic mutations of serine 13 and serine 16 by aspartic or glutamic acid substitution (S13D and S16D or S13E and S16E) decrease the toxicity of mutant huntingtin fragments in vitro (10, 16). In line with these studies, expression of a phosphomimetic (S13D and S16D) mutant form of expanded full-length huntingtin in a BACHD transgenic mouse model was shown to result in a normal phenotype, with no detectable signs of HD pathology by 12 mo (17).These findings suggest that pharmacological interventions that modulate cell sig...

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Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice

Cited by 424 publications

References 37 publications

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC

Protein misfolding inside cells: The case of huntingtin and Huntington's disease

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

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