A study of molecular changes relating to energy metabolism and cellular stress in people with Huntington’s disease: looking for biomarkers

Krzysztoń-Russjan, Jolanta; Zielonka, Daniel; Jackiewicz, Joanna; Kuśmirek, S; Bubko, Irena; Klimberg, Aneta; Marcinkowski, Jerzy T.; Anuszewska, Elżbieta

doi:10.1007/s10863-012-9479-3

Cited by 29 publications

(22 citation statements)

References 42 publications

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“…This delayed increase coincides with significant improvements in memory and learning achieved after longitudinal intervention. Our results are in accord with previous evidence demonstrating reduced BDNF/BDNF levels in Huntington's disease, in both humans and animal models [95][96][97][98][99][100] , and activity-dependent increases in BDNF expression in animals 77,82,104,105,109,110 and in human populations [106][107][108] . During the course of this investigation, however, a recent publication has questioned the utility of BDNF measurement as a biomarker for the monitoring of Huntington's disease 162 .…”

Section: Discussionsupporting

confidence: 93%

“…Consistent with previous reports [95][96][97][98][99][100][101] , the ELISA results indicated lower levels of BDNF in the whole blood of Huntington's disease individuals, relative to normative data ( Figure 26). The assay to detect changes in mean BDNF concentration over the time period of the study revealed a non-significant reduction in mean BDNF levels after the control period (p=0.838) which worsened after one round of intervention (p=0.393).…”

Section: Bdnfsupporting

confidence: 91%

“…Huntington's disease [95][96][97][98][99][100][101] and are suspected of contributing to striatal pathology 93,94,[100][101][102] .…”

Section: D-kefs Trail Makingmentioning

confidence: 99%

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First use of creatine hydrochloride in premanifest Huntington disease

Tuckfield

2015

Medical Journal of Australia

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Section: Discussionsupporting

confidence: 93%

Section: Bdnfsupporting

confidence: 91%

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First use of creatine hydrochloride in premanifest Huntington disease

Tuckfield

2015

Medical Journal of Australia

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“…As was shown by Krzysztoń-Russjan et al, BCKDK (branched chain ketoacid dehydrogenase kinase) on the transcription level was increased in nuclear blood cells of HD subjects. 31 In turn, no significant abnormalities of KGDHC were also indicated in red blood cells and cultured fibroblasts of AD. 29 In this study the negative correlation noted between BCKDHC activity and thiamine concentration found in GM14467 cells is difficult to interpret, but it proves the cell specificity of energy metabolism.…”

Section: Discussionmentioning

confidence: 95%

Role of thiamine in Huntington’s disease pathogenesis: In vitro studies

Gruber-Bzura¹,

Krzysztoń-Russjan²,

Bubko³

et al. 2017

Adv Clin Exp Med

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“…Our data indicated that the modification by TG2 impaired IP 3 R1-mediated cellular processes; therefore, we hypothesized that this regulation might lead to cellular dysregulation under pathological conditions. TG2 is up-regulated in the brain in HD model mice, including R6/2 and YAC128 mice (54)(55)(56)(57), and HD patients (49,(58)(59)(60)(61). Therefore, we tested whether IP 3 R was modified by TG2 in these HD models.…”

Section: Resultsmentioning

confidence: 99%

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

Hamada

Terauchi

Nakamura

et al. 2014

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

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The inositol 1,4,5-trisphosphate receptor (IP 3 R) in the endoplasmic reticulum mediates calcium signaling that impinges on intracellular processes. IP 3 Rs are allosteric proteins comprising four subunits that form an ion channel activated by binding of IP 3 at a distance. Defective allostery in IP 3 R is considered crucial to cellular dysfunction, but the specific mechanism remains unknown. Here we demonstrate that a pleiotropic enzyme transglutaminase type 2 targets the allosteric coupling domain of IP 3 R type 1 (IP 3 R1) and negatively regulates IP 3 R1-mediated calcium signaling and autophagy by locking the subunit configurations. The control point of this regulation is the covalent posttranslational modification of the Gln2746 residue that transglutaminase type 2 tethers to the adjacent subunit. Modification of Gln2746 and IP 3 R1 function was observed in Huntington disease models, suggesting a pathological role of this modification in the neurodegenerative disease. Our study reveals that cellular signaling is regulated by a new mode of posttranslational modification that chronically and enzymatically blocks allosteric changes in the ligand-gated channels that relate to disease states.L igand-gated ion channels function by allostery that is the regulation at a distance; the allosteric coupling of ligand binding with channel gating requires reversible changes in subunit configurations and conformations (1). Inositol 1,4,5-trisphosphate receptors (IP 3 Rs) are ligand-gated ion channels that release calcium ions (Ca 2+ ) from the endoplasmic reticulum (ER) (2, 3). IP 3 Rs are allosteric proteins comprising four subunits that assemble a calcium channel with fourfold symmetry about an axis perpendicular to the ER membrane. The subunits of three IP 3 R isoforms (IP 3 R1, IP 3 R2, and IP 3 R3) are structurally divided into three domains: the IP 3 -binding domain (IBD), the regulatory domain, and the channel domain (3-6). Fitting of the IBD X-ray structures (7, 8) to a cryo-EM map (9) indicates that the IBD activates a remote Ca 2+ channel by allostery (8); however, the current X-ray structure only spans 5% of each tetramer, such that the mechanism underlying allosteric coupling of the IBD to channel gating remains unknown.The IP 3 R in the ER mediates intracellular calcium signaling that impinges on homeostatic control in various subsequent intracellular processes. Deletion of the genes encoding the type 1 IP 3 R (IP 3 R1) leads to perturbations in long-term potentiation/ depression (3, 10, 11) and spinogenesis (12), and the human genetic disease spinocerebellar ataxia 15 is caused by haploinsufficiency of the IP 3 R1 gene (13-15). Dysregulation of IP 3 R1 is also implicated in neurodegenerative diseases including Huntington disease (HD) (16-18) and Alzheimer's disease (AD) (19)(20)(21)(22). IP 3 Rs also control fundamental cellular processes-for example, mitochondrial energy production (23, 24), autophagy regulation (24-27), ER stress (28), hepatic gluconeogenesis (29), pancreatic exocytosis (30), and macrophag...

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A study of molecular changes relating to energy metabolism and cellular stress in people with Huntington’s disease: looking for biomarkers

Abstract: Huntington's disease (HD) is a neurodegenerative disorder characterized by a progressive motor and cognitive decline and the development of psychiatric symptoms.

Cited by 29 publications

References 42 publications

First use of creatine hydrochloride in premanifest Huntington disease

First use of creatine hydrochloride in premanifest Huntington disease

Role of thiamine in Huntington’s disease pathogenesis: In vitro studies

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

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