The unfolded protein response and its potential role in Huntington's disease elucidated by a systems biology approach

Kalathur, Ravi Kiran Reddy; Giner‐Lamia, Joaquín; Machado, Susana; Barata, Tânia; Ayasolla, Kamesh; Futschik, Matthias E.

doi:10.12688/f1000research.6358.2

Cited by 27 publications

(17 citation statements)

References 93 publications

(86 reference statements)

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“…To determine if gene transcription underlies the alterations in protein expression, we performed real-time qPCR on samples from R6/2 and WT mice using isoform-specific amplification of Slc12A5 (KCC2) and Slc12A2 (NKCC1). We used previously identified stable control genes for R6/2 mice ( Rpl13a , ATP5b , Ubc , Canx ) ( 41 ) and found a significant decrease in KCC2 mRNA from R6/2 mice (7 wk old) compared with WT, consistent with bioinformatic predictions ( 27 ) ( Fig. 2 F and SI Appendix , Fig.…”

Section: Resultssupporting

confidence: 77%

“…Recent proteomic studies revealed that the KCC2 encoding gene, Slc12A5 , is highly enriched in Htt proteome ( 25 , 26 ), but despite the strong correlation, this interaction has not been validated. Furthermore, a bioinformatic analysis of the unfolded protein response (UPR)-regulated genes in HD reveals an increase in NKCC1 mRNA and a decrease in KCC2 mRNA ( 27 ), which is significant because UPR is implicated in numerous neurodegenerative diseases including HD ( 28 – 30 ). Based on the previous data linking (m)Htt and Cl − transporters ( 25 , 26 ) and the important role of inhibition in learning and memory, we hypothesized that KCC2 function is dysregulated in the HD brain, resulting in weakened inhibitory GABAergic transmission, which contributes to the hippocampal-dependent learning and memory deficits that emerge early in HD.…”

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confidence: 99%

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Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Dargaei

Bang

Mahadevan

et al. 2018

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

134

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SignificanceHuntington’s disease (HD) is a fatal neurodegenerative disorder that currently has no cure. Although HD is classically considered a motor disorder, HD patients experience learning and memory deficits years before the onset of motor symptoms, and these deficits resemble those observed in HD mouse models. In this work, using transgenic mouse models of HD, we demonstrate that the action of the neurotransmitter GABA has switched from inhibitory to excitatory. By treating HD mice with a clinically used diuretic (bumetanide), which restores inhibitory GABA, we rescued the learning and memory deficits. Our data suggest a potential therapeutic approach for the treatment of the cognitive deficits in early HD that can improve patient quality of life and reduce caregiver burden.

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Section: Resultssupporting

confidence: 77%

mentioning

confidence: 99%

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Dargaei

Bang

Mahadevan

et al. 2018

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

134

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“…Htt-NTFs engage in a wide variety of proteinprotein interactions (75,(81)(82)(83)(84)(85)(86)(87)(88)(89)(90). These "interactomes" are tissue-specific and within a tissue-type, the nodes and edges in an interaction network are known to be different for Htt-NTFs with wild-type versus mutant polyQ lengths (90).…”

Section: Understanding the Effects Of Htt-ntf Binding Partners In Termentioning

confidence: 99%

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Posey

Ruff

Harmon

et al. 2018

Journal of Biological Chemistry

122

117

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Huntingtin N-terminal fragments (Htt-NTFs) with expanded polyglutamine tracts form a range of neurotoxic aggregates that are associated with Huntington's disease. Here, we show that aggregation of Htt-NTFs, irrespective of polyglutamine length, yields at least three phases (designated M, S, and F) that are delineated by sharp concentration thresholds and distinct aggregate sizes and morphologies. We find that monomers and oligomers make up the soluble M-phase, ~25 nm spheres dominate in the soluble S-phase, and long, linear fibrils make up the insoluble F-phase. Previous studies showed that profilin, an abundant cellular protein, reduces Htt-NTF aggregation and toxicity in cells. We confirm that profilin achieves its cellular effects through direct binding to the C-terminal proline-rich region of Htt-NTFs. We show that profilin preferentially binds to Htt-NTF M-phase species and destabilizes aggregation and phase separation by shifting the concentration boundaries for phase separation to higher values through a process known as polyphasic linkage. Our experiments, aided by coarse-grained computer simulations and theoretical analysis, suggest that preferential binding of profilin to the Mphase species of Htt-NTFs is enhanced through a combination of specific interactions between profilin and polyproline segments and auxiliary interactions between profilin and polyglutamine tracts. Polyphasic linkage may be a general strategy that cells utilize to regulate phase behavior of aggregation-prone proteins. Accordingly, detailed knowledge of phase behavior and an understanding of how ligands modulate phase boundaries may pave the way for developing new therapeutics against a variety of aggregation-prone proteins.Many diseases are associated with protein misfolding and aggregation (1,2). The aggregation process is often characterized by the presence of one or more threshold concentrations at which a sharp, discontinuous change to some aspect of the assembly state (e.g., size, conformational characteristics, material properties) occurs (3-6). Such a change can be described using the concepts of phase transitions. Phase separation, a subcategory of phase transitions, has recently received considerable attention due to increasing recognition of its importance in cell biology (7)(8)(9)(10)(11)(12)(13). Phase separation refers to aggregation-related changes in molecular density that give rise to the coexistence of dilute macromolecule-deficient phases and dense macromolecule-rich phases (3,14,15). Examples of multiple coexisting phases have been observed in biological contexts (15)(16)(17)(18), and these phases can be liquid, solid, or semisolid (e.g., a gel) (10,(19)(20)(21)(22)(23)(24)(25) Modulation of Htt-NTF aggregation via polyphasic linkage2 separation are quantified in terms of saturation concentrations (14,19,26). For a given two-phase system, the saturation concentration is the bulk concentration of the protein beyond which the solution separates into two coexisting phases. The lower the saturation concentration, t...

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“…Sorcin is overexpressed in a PD cell model induced by 1-methyl-4-phenylpyridinium ion (MPP + ) in SH-SY5Y cells [53] , which is one of the most differentially expressed proteins in PD vs. normal human substantia nigra [54] and in PD vs. human brain samples [55] , and is overexpressed in AD brain samples [56][57][58] , in particular in sporadic AD [59] and in AD brains with severe cerebral amyloid angiopathy [60] , as well as in frontal cortical tissues from postmortem cases of frontotemporal dementia [61] . Further, Sorcin is overexpressed in 7 different Huntington's disease human and mice models, where it has been associated with the unfolded protein response [62] . Sorcin also interacts with the ionotropic glutamate receptor NMDAR1 Ca 2+ channel, important in several cascade pathways and in synaptic plasticity, in caudate-putamen nucleus [63] , and with annexins A7 and A11, involved in Ca 2+ homeostasis in astrocytes [64] .…”

Section: The Roles Of Sorcin In the Cell: Sorcin Localization Cell Cmentioning

confidence: 99%

Molecular bases of Sorcin-dependent resistance to chemotherapeutic agents

Genovese¹,

Ilari²,

Battista³

et al. 2018

CDR

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Soluble resistance-related calcium binding protein (Sorcin) is a protein initially labelled "resistance-related", since it is co-amplified with ABCB1 in multidrug (MD)-resistant cells. While for years Sorcin overproduction was believed to be a by-product of the co-amplification of its gene with the P-glycoprotein gene, many recent studies view Sorcin as an oncoprotein, playing an important role in MD resistance (MDR). Sorcin is one of the most highly expressed calciumbinding proteins, which is overexpressed in many human tumors and MD resistant cancers, and represents a novel MDR marker. Sorcin expression in tumors inversely correlates with patients' response to chemotherapies and overall prognosis. Sorcin is highly expressed in MDR cell lines over their parent cells. Sorcin overexpression by gene transfection increases drug resistance to a variety of chemotherapeutic drugs in many cancer lines. On the other hand, Sorcin silencing leads to reversal of drug resistance in many cell lines. This review describes: (1) the roles of Sorcin in the cell; (2) the studies showing Sorcin overexpression in tumors and cancer cells; (3) the studies showing the effects of Sorcin overexpression and silencing; (4) the molecular effects of Sorcin overexpression; and (5) the structural and genetic bases of Sorcin-dependent MDR.

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The unfolded protein response and its potential role in Huntington's disease elucidated by a systems biology approach

Abstract: Huntington ś disease (HD)

Cited by 27 publications

References 93 publications

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model

Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers

Molecular bases of Sorcin-dependent resistance to chemotherapeutic agents

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