How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Lontay, Beáta; Kiss, Andrea; Virág, László; Tar, Krisztina

doi:10.3390/ijms21124282

Cited by 34 publications

(28 citation statements)

References 267 publications

(324 reference statements)

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“…TGF-β1 induces the p85 subunit of PI3K to be recruited into focal adhesion kinase (FAK) ( Vallée and Lecarpentier 2019 ). PI3K activates Akt by phosphorylation at the thr308 and ser473 sites ( Lontay et al, 2020 ). Moreover, TGF-β1 activates Akt signaling through p38 mitogen–activated protein kinase (MAPK) and FAK ( Choi et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Guhong Injection Protects Against Apoptosis in Cerebral Ischemia by Maintaining Cerebral Microvasculature and Mitochondrial Integrity Through the PI3K/AKT Pathway

et al. 2021

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Guhong injection (GHI) can be used for the treatment of ischemic stroke. We investigated the antiapoptotic activity of GHI, its ability to repair the cerebral microvessels and mitochondria, and the PI3K/AKT signaling pathway of GHI against cerebral ischemia. Western blot and immunohistochemical analyses were used to determine the expression of cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), cytochrome c (Cyt-c), basic fibroblast growth factor (BFGF), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), and proteins in the PI3K/AKT signaling pathway. Transmission electron microscopy and scanning electron microscopy were used to evaluate the structures of the cerebral microvasculature and cells. Hoechst 33342 staining was used to evaluate the nuclear morphology. FITC-AV/PI double staining was used to measure the antiapoptotic effects. The fluorescent dye JC-1 was used to measure mitochondrial membrane potential. The enzyme-linked immunosorbent assay (ELISA) was used to detect the activities of matrix metalloproteinase-9 (MMP-9). Biochemical assay kits were used to detect the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA). Compared with the middle cerebral artery occlusion (MCAO) group, there was decreased infarct volume and significantly improved neurological deficits in the GHI group. In addition, the expression of Bcl-2 was significantly upregulated, while the expression of Cyt-c, Bax, and cleaved caspase-3 was notably downregulated. GHI administration attenuated the pathological change and morphology of the cerebral microvasculature, and immunohistochemical staining indicated that the expressions of BFGF, VEGF, and TGF-β1 were significantly increased. The cell morphology, cell viability, cell nuclei characteristics, and mitochondrial morphology normalized following GHI treatment, which decreased the release of Cyt-c and the mitochondrial membrane potential. The levels of LDH, MMP-9, and MDA decreased, while SOD increased. Moreover, GHI administration inhibited the activation of the PI3K/AKT signaling pathway in rat brain microvascular endothelial cells (rBMECs) following oxygen/glucose deprivation (OGD) injury. Therefore, our results show that GHI administration resulted in antiapoptosis of cerebral cells and repair of cerebral microvessels and mitochondria via the PI3K/AKT signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Guhong Injection Protects Against Apoptosis in Cerebral Ischemia by Maintaining Cerebral Microvasculature and Mitochondrial Integrity Through the PI3K/AKT Pathway

et al. 2021

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“…Protective effects of promoting palmitoylation of HTT and other substrates may be mediated by increased mHTT clearance, or reduced proteolytic cleavage of mHTT by caspase 6 (CASP6) at D586. We have indeed recently shown that CASP6 is palmitoylated by HIP14, resulting in CASP6 inactivation (Lontay et al, 2020;Skotte et al, 2017) Brain lysates from 6-month-old YAC128 and littermate controls (WT), BACHD and WT, humanized Hu97/18 and Hu18/18, Hu128/21 and Hu21/21 mice were subjected to the ABE assay. The palmitoylation signal (HAM+) is shown in the top panels for each mouse line and protein, and the total protein immunoprecipitated is presented in the corresponding bottom panel.…”

Section: Discussionmentioning

confidence: 99%

“…Martin et al, 2014;Yanai et al, 2006). These PTMs regulate subcellular localization, protein-protein interactions, aggregation and clearance which modulates the toxicity of mutant HTT (mHTT) (Atwal et al, 2007;Cariulo et al, 2017;Caron et al, 2013;Kratter et al, 2016;Lontay et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

Lemarié¹,

Caron²,

Sanders

et al. 2021

Preprint

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Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple posttranslational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in humanized rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be modulated by pharmacological intervention. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that aging further reduces HTT palmitoylation. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons.

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“…This observation in combination with previous observations from our group on the cross-talk between T3 phosphorylation and K6 acetylation underscores the importance of conducting further studies to elucidate the role of cross-talk among PTMs in the regulation of Htt aggregation, especially since several PTMs are known to cluster in a short sequence motifs throughout the Htt protein (Figure 1a). 17,40 For example, most of the proteolytic sites identified on Htt are flanked by phosphorylation residues, indicating possible cross-talk between phosphorylation and proteolysis. 6 Although several studies have investigated the aggregation propensity of various N-terminal Htt fragments in different cellular and animal HD models, characterization of the aggregation properties of these fragments was limited to quantifying the number of inclusions and their size or shape.…”

Section: Discussionmentioning

confidence: 99%

A new chemoenzymatic semisynthetic approach provides novel insight into the role of phosphorylation beyond exon1 of Huntingtin and reveals N-terminal fragment length-dependent distinct mechanisms of aggregation

Rajasekhar

Gopinath

Ricci

et al. 2021

Preprint

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Huntingtons disease is a neurodegenerative disorder caused by the expansion of a polyglutamine (poly Q) repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Htt exon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1. We also present a new chemoenzymatic semisynthetic strategy that enables site-specific phosphorylation of Htt beyond Httex1. These advances yielded novel insights into how PTMs and structured domains beyond Httex1 influence aggregation mechanisms, kinetics, and fibril morphology of longer N-terminal Htt fragments. We demonstrate that phosphorylation at T107 significantly slowed its aggregation, whereases phosphorylation at T107 and S116 accelerated the aggregation of Htt171, underscoring the importance of crosstalk between different PTMs. We demonstrate that mutant Htt171 proteins aggregate via a different mechanism and form oligomers and fibrillar aggregates with morphological properties that are distinct from that of mutant Httex1. These observations suggest that different N-terminal fragments could have distinct mechanisms of aggregation and that a single polyQ-targeting anti-aggregation strategy may not effectively inhibit the aggregation of all N-terminal Htt fragments. Finally, our results underscore the importance of further studies to investigate the aggregation mechanisms of Htt fragments and how the various fragments interact with each other and influence Htt toxicity, pathology formation, and disease progression.

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How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Cited by 34 publications

References 267 publications

Guhong Injection Protects Against Apoptosis in Cerebral Ischemia by Maintaining Cerebral Microvasculature and Mitochondrial Integrity Through the PI3K/AKT Pathway

Guhong Injection Protects Against Apoptosis in Cerebral Ischemia by Maintaining Cerebral Microvasculature and Mitochondrial Integrity Through the PI3K/AKT Pathway

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

A new chemoenzymatic semisynthetic approach provides novel insight into the role of phosphorylation beyond exon1 of Huntingtin and reveals N-terminal fragment length-dependent distinct mechanisms of aggregation

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