Polyglutamine Expansion Alters the Dynamics and Molecular Architecture of Aggregates in Dentatorubropallidoluysian Atrophy

Hinz, Justyna; Lehnhardt, Lothar; Zakrzewski, Silke S.; Zhang, Gong; Ignatova, Zoya

doi:10.1074/jbc.m111.318915

Cited by 7 publications

(7 citation statements)

References 58 publications

(74 reference statements)

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“…The quantification of the detergent-soluble Q-YFP or Q-CFP monomers was performed from the recorded tif-images of the immunoblots and represents the integrated pixel intensity of the corresponding band with subtracted intensity of the background. Note that the quantification for polyQ proteins can be only approximate because of the intrinsic length-dependent propensity to form SDS-insoluble aggregates which remain unresolved on the gel; also polyQ proteins with non-pathological polyQ lengths form small fractions of SDS-resistant aggregates 50 .…”

Section: Methodsmentioning

confidence: 99%

Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans

Adamla

Ignatova

2015

Sci Rep

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Aging is a highly controlled biological process characterized by a progressive deterioration of various cellular activities. One of several hallmarks of aging describes a link to transcriptional alteration, suggesting that it may impact the steady-state mRNA levels. We analyzed the mRNA steady-state levels of polyCAG-encoding transgenes and endogenous genes under the control of well-characterized promoters for intestinal (vha-6), muscular (unc-54, unc-15) and pan-neuronal (rgef-1, unc-119) expression in the nematode Caenorhabditis elegans. We find that there is not a uniform change in transcriptional profile in aging, but rather a tissue-specific difference in the mRNA levels of these genes. While levels of mRNA in the intestine (vha-6) and muscular (unc-54, unc-15) cells decline with age, pan-neuronal tissue shows more stable mRNA expression (rgef-1, unc-119) which even slightly increases with the age of the animals. Our data on the variations in the mRNA abundance from exemplary cases of endogenous and transgenic gene expression contribute to the emerging evidence for tissue-specific variations in the aging process.

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Section: Methodsmentioning

confidence: 99%

Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans

Adamla

Ignatova

2015

Sci Rep

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“…For isolation of mitochondria, an optimized protocol for HeLa cells was used following the instructions of Wieckowski et al [63]. To obtain the nuclear fraction we followed the instructions of Hinz et al [64]. All fractions were frozen in liquid nitrogen and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

The L-Cysteine Desulfurase NFS1 Is Localized in the Cytosol where it Provides the Sulfur for Molybdenum Cofactor Biosynthesis in Humans

et al. 2013

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In humans, the L-cysteine desulfurase NFS1 plays a crucial role in the mitochondrial iron-sulfur cluster biosynthesis and in the thiomodification of mitochondrial and cytosolic tRNAs. We have previously demonstrated that purified NFS1 is able to transfer sulfur to the C-terminal domain of MOCS3, a cytosolic protein involved in molybdenum cofactor biosynthesis and tRNA thiolation. However, no direct evidence existed so far for the interaction of NFS1 and MOCS3 in the cytosol of human cells. Here, we present direct data to show the interaction of NFS1 and MOCS3 in the cytosol of human cells using Förster resonance energy transfer and a split-EGFP system. The colocalization of NFS1 and MOCS3 in the cytosol was confirmed by immunodetection of fractionated cells and localization studies using confocal fluorescence microscopy. Purified NFS1 was used to reconstitute the lacking molybdoenzyme activity of the Neurospora crassa nit-1 mutant, giving additional evidence that NFS1 is the sulfur donor for Moco biosynthesis in eukaryotes in general.

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“…Importantly, the lack of SDS-resistance of Htt51S aggregates alone correlated with the observed motility of the nuclear aggregates composed solely of Htt51AGC-YFP. Detergent-labile inclusions are highly mobile, whereas amyloid SDS-resistant aggregates display restricted mobility (24). Most likely, the cytoplasmic aggregates with restricted mobility (Fig.…”

Section: ؉1 Frameshifting In Huntingtinmentioning

confidence: 99%

An Expanded CAG Repeat in Huntingtin Causes +1 Frameshifting

Saffert

Adamla

Schieweck

et al. 2016

Journal of Biological Chemistry

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Maintenance of triplet decoding is crucial for the expression of functional protein because deviations either into the ؊1 or ؉1 reading frames are often non-functional. We report here that expression of huntingtin (Htt) exon 1 with expanded CAG repeats, implicated in Huntington pathology, undergoes a sporadic ؉1 frameshift to generate from the CAG repeat a transframe AGC repeat-encoded product. This ؉1 recoding is exclusively detected in pathological Htt variants, i.e. those with expanded repeats with more than 35 consecutive CAG codons. An atypical ؉1 shift site, UUC C at the 5 end of CAG repeats, which has some resemblance to the influenza A virus shift site, triggers the ؉1 frameshifting and is enhanced by the increased propensity of the expanded CAG repeats to form a stem-loop structure. The ؉1 trans-frame-encoded product can directly influence the aggregation of the parental Htt exon 1.

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Polyglutamine Expansion Alters the Dynamics and Molecular Architecture of Aggregates in Dentatorubropallidoluysian Atrophy

Cited by 7 publications

References 58 publications

Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans

Somatic expression of unc-54 and vha-6 mRNAs declines but not pan-neuronal rgef-1 and unc-119 expression in aging Caenorhabditis elegans

The L-Cysteine Desulfurase NFS1 Is Localized in the Cytosol where it Provides the Sulfur for Molybdenum Cofactor Biosynthesis in Humans

An Expanded CAG Repeat in Huntingtin Causes +1 Frameshifting

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