Molecular Dynamics Simulations Applied to Structural and Dynamical Transitions of the Huntingtin Protein: A Review

Moldovean, Sanda Nastasia; Chiş, Vasile

doi:10.1021/acschemneuro.9b00561

Cited by 16 publications

(17 citation statements)

References 198 publications

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“…The formation of polyglutamine (polyQ) tracts is one of the most debated issues in the literature, focusing on amyloid-like fibrils formation. , Considering that the mutation consists of additional glutamine (Q) residues, the mutated structures are able to form complementary interfaces with identical segments. , Consequently, amyloid-like fibrils are considered to be formed through assembly of steric zipper two self-complementary β-sheets . On the other hand, this particular conformational assembly mechanism was found for a large variety of proteins, although not all of them presented the β-sheet configuration.…”

Section: Introductionmentioning

confidence: 99%

Specific Key-Point Mutations along the Helical Conformation of Huntingtin-Exon 1 Protein Might Have an Antagonistic Effect on the Toxic Helical Content’s Formation

Moldovean

Chiş

2020

ACS Chem. Neurosci.

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The polyglutamine tract length represents a key regulator for the Huntington’s disease toxicity level and its aggregation rates, often being related to helical structural conformations. In this study, we performed all-atom MD simulations on mutant Huntingtin-Exon1 protein with additional mutation spots, aiming to observe the corresponding structural and dynamical changes at the level of the helix. The simulated structures consist of three sets of Q residue mutations into P residues (4P, 7P, and 9P), with each set including different spots of mutations: random along the mutant sequence (R models), at the edges of the helix (E models), as well as at the edges and in the middle of the helix (EM models). At the helical level, our results predict less compactness profiles for a higher number of P mutations (7P and 9P models) with particular mutation spots at the edges and at the edges-middle of the helix. Moreover, the C-alpha atom distances decreased for 7P and 9P models in comparison to 4P models, and the RMSF values show the highest fluctuation rates for 9P models with point mutations at the edges and in the middle of the helix. The secondary structure analysis suggests greater structural transitions from α-helices to bends, turns, and random coils for 7P and 9P models, particularly for point mutations considered at the edges and in the middle of the helical content. The obtained results support our hypothesis that specific key-point mutations along the helical conformation might have an antagonistic effect on the toxic helical content’s formation.

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Section: Introductionmentioning

confidence: 99%

Specific Key-Point Mutations along the Helical Conformation of Huntingtin-Exon 1 Protein Might Have an Antagonistic Effect on the Toxic Helical Content’s Formation

Moldovean

Chiş

2020

ACS Chem. Neurosci.

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“…HD is primarily caused by the mutation in a single autosomal dominant gene leading to the formation of the mutant huntingtin gene ( m HTT). m HTT with expanded CAG trinucleotide repeats (>36 CAG), encodes elongated polyQ repeats in the N -terminus, which in turn triggers aggregation of the huntingtin protein ( Moldovean and Chiş, 2020 ). The pathology of HD is characterized by huntingtin protein aggregates.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of a Fluorine-18 Radioligand for Imaging Huntingtin Aggregates by Positron Emission Tomographic Imaging

et al. 2021

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Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (mHTT), which is the hallmark pathology of neurodegenerative Huntington’s disease (HD). Development of a high affinity 18F radiotracer would enable the study of Huntington’s disease pathology using a non-invasive imaging modality, positron emission tomography (PET) imaging. Herein, we report the first synthesis of fluorine-18 imaging agent, 6-(5-((5-(2,2-difluoro-2-(fluoro-18F)ethoxy)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one ([18F]1), a radioligand for HD and its preclinical evaluation in vitro (autoradiography of post-mortem HD brains) and in vivo (rodent and non-human primate brain PET). [18F]1 was synthesized in a 4.1% RCY (decay corrected) and in an average molar activity of 16.5 ± 12.5 GBq/μmol (445 ± 339 Ci/mmol). [18F]1 penetrated the blood-brain barrier of both rodents and primates, and specific saturable binding in post-mortem brain slices was observed that correlated to mHTT aggregates identified by immunohistochemistry.

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“…When more than 40 CAG repeats are present in Htt alleles, it is inevitable to develop the disease [1]. Expanded CAG repeats in Htt code for an abnormal polyglutamine (polyQ) stretch, and therefore increase the tendency of mutant Htt (mHtt) protein to self-aggregate and deposit in the neuron [2]. Although the detailed mechanisms are still not very clear, these mHtt proteins are found to be toxic to neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

miR-302 Attenuates Mutant Huntingtin-Induced Cytotoxicity through Restoration of Autophagy and Insulin Sensitivity

Chang

Tsou

Chen

et al. 2021

IJMS

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Huntington’s disease (HD) is an autosomal-dominant brain disorder caused by mutant huntingtin (mHtt). Although the detailed mechanisms remain unclear, the mutational expansion of polyglutamine in mHtt is proposed to induce protein aggregates and neuronal toxicity. Previous studies have shown that the decreased insulin sensitivity is closely related to mHtt-associated impairments in HD patients. However, how mHtt interferes with insulin signaling in neurons is still unknown. In the present study, we used a HD cell model to demonstrate that the miR-302 cluster, an embryonic stem cell-specific polycistronic miRNA, is significantly downregulated in mHtt-Q74-overexpressing neuronal cells. On the contrary, restoration of miR-302 cluster was shown to attenuate mHtt-induced cytotoxicity by improving insulin sensitivity, leading to a reduction of mHtt aggregates through the enhancement of autophagy. In addition, miR-302 also promoted mitophagy and stimulated Sirt1/AMPK-PGC1α pathway thereby preserving mitochondrial function. Taken together, these results highlight the potential role of miR-302 cluster in neuronal cells, and provide a novel mechanism for mHtt-impaired insulin signaling in the pathogenesis of HD.

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Molecular Dynamics Simulations Applied to Structural and Dynamical Transitions of the Huntingtin Protein: A Review

Cited by 16 publications

References 198 publications

Specific Key-Point Mutations along the Helical Conformation of Huntingtin-Exon 1 Protein Might Have an Antagonistic Effect on the Toxic Helical Content’s Formation

Specific Key-Point Mutations along the Helical Conformation of Huntingtin-Exon 1 Protein Might Have an Antagonistic Effect on the Toxic Helical Content’s Formation

Synthesis and Evaluation of a Fluorine-18 Radioligand for Imaging Huntingtin Aggregates by Positron Emission Tomographic Imaging

miR-302 Attenuates Mutant Huntingtin-Induced Cytotoxicity through Restoration of Autophagy and Insulin Sensitivity

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