The localization and interactions of huntingtin

Al, Jones

doi:10.1098/rstb.1999.0454

Cited by 17 publications

(3 citation statements)

References 60 publications

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“…CBS was identified as an interacting partner for Huntingtin protein (18). Accumulation of mutant Huntingtin containing an expanded polyglutamine tract is associated with the neurodegenerative disease, and relocalization of a pathogenic fragment of the protein from the cytoplasm to intranuclear inclusions is observed (53). Interestingly, SUMO modification of a pathogenic fragment of Huntingtin diminishes aggregate formation and competes for ubiquitination at the same site (22).…”

Section: Discussionmentioning

confidence: 99%

Human Cystathionine β-Synthase Is a Target for Sumoylation

2006

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Cystathionine beta-synthase (CBS) catalyzes the first irreversible step in the transsulfuration pathway and commits the toxic metabolite, homocysteine, to the synthesis of cysteine. Mutations in CBS are the most common cause of severe hereditary hyperhomocysteinemia. The molecular basis of the organ-specific pathologies associated with CBS deficiency is unknown as is the significance of the reported interaction between CBS and Huntingtin protein. In this study, we have used the yeast two-hybrid approach to screen for proteins that interact with CBS and have identified several components of the sumoylation pathway including Ubc9, PIAS1, PIAS3, Pc2, and RanBPM. We demonstrate that CBS is modified by the small ubiquitin-like modifier-1 protein (SUMO-I) under both in vitro and in vivo conditions. Deletion analysis of CBS indicates that the C-terminal regulatory domain is required for interaction with proteins in the sumoylation machinery. Sumoylated CBS is present in the nucleus where it is associated with the nuclear scaffold. The discovery that CBS is a target of sumoylation adds another layer to the complex regulation of this enzyme and reveals a previously unknown residence for this protein, i.e., in the nucleus.

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Section: Discussionmentioning

confidence: 99%

Human Cystathionine β-Synthase Is a Target for Sumoylation

2006

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“…20 In human neurons, N-terminal Htt fragments have been identified in neural intranuclear inclusions (NIIs) and dystrophic neurites (DNs) (Figure 2 (a)), with their C-terminal counterparts in the cytoplasm. 21,22 Remarkably, an HttEx1 fragment also forms via erroneous splicing of the mutant protein. 23 The findings described above led to many studies of HttEx1 in model animals and neuronal cells, which commonly observe HD-like symptoms, neuronal degeneration, and HttEx1 inclusions.…”

Section: Hd Mutant Proteinmentioning

confidence: 99%

Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease

Matlahov

Wel

2019

Exp Biol Med (Maywood)

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Huntington’s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington’s disease patients and their families, with the disease typically being fatal within 10–15 years from onset. Huntington’s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington’s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington’s disease are found within patients’ neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms. Impact statement Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington’s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.

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“…NCOR1 is part of the HD pathway and encodes the protein nuclear receptor corepressor 1, which mediates transcriptional repression of thyroid-hormone and retinoic acid receptors. This protein reportedly interacts with mutant HTT ( 52 , 53 ) to alter nuclear receptor function and is also differentially located in patient brain tissue ( 53 , 54 ). ADORA2B encodes adenosine receptor subtype A2B, a protein that interacts with netrin-1, which is involved in axon elongation.…”

Section: Discussionmentioning

confidence: 99%

Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

et al. 2018

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Huntington’s disease (HD) is a neurodegenerative disorder caused by an expansion mutation of the cytosine–adenine–guanine (CAG) trinucleotide in the HTT gene. Decline in cognitive and motor functioning during the prodromal phase has been reported, and understanding genetic influences on prodromal disease progression beyond CAG will benefit intervention therapies. From a prodromal HD cohort (N = 715), we extracted gray matter (GM) components through independent component analysis and tested them for associations with cognitive and motor functioning that cannot be accounted for by CAG-induced disease burden (cumulative effects of CAG expansion and age). Furthermore, we examined genetic associations (at the genomic, HD pathway, and candidate region levels) with the GM components that were related to functional decline. After accounting for disease burden, GM in a component containing cuneus, lingual, and middle occipital regions was positively associated with attention and working memory performance, and the effect size was about a tenth of that of disease burden. Prodromal participants with at least one dystonia sign also had significantly lower GM volume in a bilateral inferior parietal component than participants without dystonia, after controlling for the disease burden. Two single-nucleotide polymorphisms (SNPs: rs71358386 in NCOR1 and rs71358386 in ADORA2B) in the HD pathway were significantly associated with GM volume in the cuneus component, with minor alleles being linked to reduced GM volume. Additionally, homozygous minor allele carriers of SNPs in a candidate region of ch15q13.3 had significantly higher GM volume in the inferior parietal component, and one minor allele copy was associated with a total motor score decrease of 0.14 U. Our findings depict an early genetical GM reduction in prodromal HD that occurs irrespective of disease burden and affects regions important for cognitive and motor functioning.

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The localization and interactions of huntingtin

Cited by 17 publications

References 60 publications

Human Cystathionine β-Synthase Is a Target for Sumoylation

Human Cystathionine β-Synthase Is a Target for Sumoylation

Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease

Genetics Modulate Gray Matter Variation Beyond Disease Burden in Prodromal Huntington’s Disease

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