Molecular Mechanism of Huntington’s Disease — A Computational Perspective

Rossetti, Giulia; Magistrato, Alessandra

doi:10.5772/32025

Cited by 4 publications

(13 citation statements)

References 153 publications

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“…In comparison to the study of Kang et al, in this study the temperature was kept around 300 K and the GROMOS96 force field was selected because of its explicit representation of acidic hydrogen atoms . Similarly to other studies, the systems were solvated with the simple point-charge (SPC) water model in a periodic box (rectangular in this case; cubic in other studies) . The long-range electrostatic interactions were usually treated with particle mesh Ewald (PME) method with the real part of calculations set at 0.9 nm.…”

Section: Resultsmentioning

confidence: 99%

“…In explicit water, MD simulations are limited to hundreds of nanoseconds. In contrast, the biological concepts are developed on larger time scales; thus the most relevant results may be achieved by combining the MD simulations with enhanced computational techniques. , In addition, the use of simplified interaction potentials might be required. ,, …”

Section: Resultsmentioning

confidence: 99%

“…Certainly, the electronic structure techniques are much more computationally demanding than the classical MD simulations. This limitation comes with the system’s size restriction to hundreds of atoms and also the time scale of ab initio MD being limited to tens of picoseconds. ,, A solution to this drawback would be to treat the systems by using hybrid techniques such as quantum-classical (QM/MM) MD simulations (classical and ab initio MD). Several computational studies ,− have used the QM/MM method to understand the electronic factors that contribute to the β-sheet conformational stability, an issue that has become of a fundamental interest in the research field of neurodegeneration diseases .…”

Section: Resultsmentioning

confidence: 99%

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

Moldovean

Chiş

2019

ACS Chem. Neurosci.

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Over the recent years, Huntington's disease (HD) has become widely discussed in the scientific literature especially because at the mutant level there are several contradictions regarding the aggregation mechanism. The specific role of the physiological huntingtin protein remains unknown, due to the lack of characterization of its entire crystallographic structure, making the experimental and theoretical research even harder when taking into consideration its involvement in multiple biological functions and its high affinity for different interacting partners. Different types of models, containing fewer (not more than 35 Qs) polyglutamine residues for the WT structure and above 35 Qs for the mutants, were subjected to classical or advanced MD simulations to establish the proteins' structural stability by evaluating their conformational changes. Outside the polyQ tract, there are two other regions of interest (the N17 domain and the polyP rich domain) considered to be essential for the aggregation kinetics at the mutant level. The polymerization process is considered to be dependent on the polyQ length. As the polyQ tract's dimension increases, the structures present more β-sheet conformations. Contrarily, it is also considered that the aggregation stability is not necessarily dependent on the number of Qs, while the initial stage of the aggregation seed might play the decisive role. A general assumption regarding the polyP domain is that it might preserve the polyQ structures soluble by acting as an antagonist for β-sheet formation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Moldovean

Chiş

2019

ACS Chem. Neurosci.

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“…The mHTT inclusions can induce a physical block of axonal transport between the cell body and the synaptic cleft and recruit other polyQ-containing proteins (i.e., transcription factors), which then interact with mHTT and might lose their physiological functions, leading to cell death [ 89 , 90 ]. The mHTT inclusions might thus function as sinks where vital proteins are sequestrated, compromising cell survival [ 91 ].…”

Section: Huntington’s Diseasementioning

confidence: 99%

Emerging Roles of Exosomes in Huntington’s Disease

Ananbeh

Vodička

Skalníková

2021

IJMS

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Huntington’s disease (HD) is a rare hereditary autosomal dominant neurodegenerative disorder, which is caused by expression of mutant huntingtin protein (mHTT) with an abnormal number of glutamine repeats in its N terminus, and characterized by intracellular mHTT aggregates (inclusions) in the brain. Exosomes are small extracellular vesicles that are secreted generally by all cell types and can be isolated from almost all body fluids such as blood, urine, saliva, and cerebrospinal fluid. Exosomes may participate in the spreading of toxic misfolded proteins across the central nervous system in neurodegenerative diseases. In HD, such propagation of mHTT was observed both in vitro and in vivo. On the other hand, exosomes might carry molecules with neuroprotective effects. In addition, due to their capability to cross blood-brain barrier, exosomes hold great potential as sources of biomarkers available from periphery or carriers of therapeutics into the central nervous system. In this review, we discuss the emerging roles of exosomes in HD pathogenesis, diagnosis, and therapy.

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“…More recently, it was demonstrated using enhanced sampling techniques that the amino acid sequences flanking the huntingtin repeats influence the misfolding propensity of the polyQ-htt, in agreement with experimental observations Lakhani et al, 2010;Shirvanyants et al, 2012). Applications of computational methods toward understanding the molecular mechanisms of HD are discussed by Rossetti and Magistrato (2012).…”

Section: Huntingtin and Huntington's Diseasementioning

confidence: 61%

Computational approaches to understanding protein aggregation in neurodegeneration

Redler

Shirvanyants

Dağliyan

et al. 2014

Journal of Molecular Cell Biology

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The generation of toxic non-native protein conformers has emerged as a unifying thread among disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Atomic-level detail regarding dynamical changes that facilitate protein aggregation, as well as the structural features of large-scale ordered aggregates and soluble non-native oligomers, would contribute significantly to current understanding of these complex phenomena and offer potential strategies for inhibiting formation of cytotoxic species. However, experimental limitations often preclude the acquisition of high-resolution structural and mechanistic information for aggregating systems. Computational methods, particularly those combine both all-atom and coarse-grained simulations to cover a wide range of time and length scales, have thus emerged as crucial tools for investigating protein aggregation. Here we review the current state of computational methodology for the study of protein self-assembly, with a focus on the application of these methods toward understanding of protein aggregates in human neurodegenerative disorders.

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Molecular Mechanism of Huntington’s Disease — A Computational Perspective

Cited by 4 publications

References 153 publications

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

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

Emerging Roles of Exosomes in Huntington’s Disease

Computational approaches to understanding protein aggregation in neurodegeneration

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