A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide

Understanding the atomistic resolution changes during the self-assembly of amyloid peptides or proteins is important to develop compounds or conditions to alter the aggregation pathways and suppress the toxicity, and potentially aid in the development of drugs. However, the complexity of protein aggregation and the transient order/disorder of oligomers along pathways to fibril are very challenging. In this perspective, we discuss computational studies of amyloid polypeptides carried out under various conditions, including conditions closely mimicking in vivo, and point out the challenges in obtaining physiologically-relevant results, focusing mainly on the amyloid-beta Aβ peptides. 1.IntroductionAmyloid fibril with a cross β-structure and intermolecular H-bonds parallel to the long fibril axis is a hallmark of many sequences differing in amino acid length and composition involved in neurogenerative diseases. These involve Aβ and tau proteins in Alzheimer's disease (AD), α-synuclein in Parkinson disease, superoxide dismutase 1 (SOD1) protein in amyotrophic lateral sclerosis, transthyretin protein in cardiac and systemic amyloidosis, prion protein in prion disease, and human islet amyloid polypeptide (hIAPP) in type 2 diabetes, among others.Fragments of these proteins form fibrils as well, which represent ideal systems for computational studies. 1 In this perspective, we mainly focus on the Aβ peptides. Results and Discussion Protein self-assembly under quiescent solution conditionsThe aggregation kinetics of amyloid proteins in aqueous solution, as measured by Thioflavin T (ThT) fluorescence assays, displays a sigmoidal curve with a lag-phase where monomers undergo conformational conversion and self-assemble into oligomers until the growth phase where the fibril elongates. This is followed by the saturation phase where the system is in equilibrium between fibrils and a low concentration of monomers. Aggregation is described by microscopic events involving primary nucleation, elongation and dissociation of a fibril by one monomer, and secondary (fibril fragmentation and fibril surface-catalyzed) nucleation. The rates of the different microscopic processes are obtained by fitting the experimental aggregation kinetic curves using multiple initial monomer concentrations. It was shown the aggregation kinetics is sensitive to variations in temperature, pH, protein concentration, ionic strength, and the presence of cofactors and preformed aggregates. 2 General questions probing amyloid fibril formation of short peptides adopting straight β-strands in the bulk solution were addressed by on-lattice models and Monte Carlo simulations. It was demonstrated that the energy difference between the monomeric native state and the fibril-prone (N*) state, and therefore the population of the ensemble of N* structures in the full spectrum of conformations, are the major determinants of the time for fibril formation. 3,4 Based on a cubic lattice that considers the formation of H-bonds and pairwise side chain interactions, 5 and replic...

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“…120,125,142 These combined studies could help design more efficient drugs targeting Aβ monomer and oligomers. 135,143…”

Section: Discussionmentioning

confidence: 99%

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

2022

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“…As both the Aβ and dynorphin peptides are known to interact with membranes [45] , [46] – Aβ is even produced by enzymatic cleavage of the AβPP (Amyloid-β precursor protein) membrane protein - it appears likely that in vivo, the two types of peptides will encounter each other and interact in membrane locations. In the amyloid field, the study of peptide-peptide cross-interactions is key [3] , [11] , [12] , [47] , [48] to characterize the physiological environment and determine which players can act as pro-amyloid or anti-amyloid agents opening new therapeutic windows in neurodegenerative disorders, such as studies on the cross-interaction between α-synuclein and endogenous peptides used as peptide-therapeutic scaffolds for Parkinson’s disease [49] .…”

Section: Discussionmentioning

confidence: 99%

Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity

Gallego-Villarejo

Wallin²,

Król³

et al. 2022

Computational and Structural Biotechnology Journal

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“…Recent efforts of using small molecules to stabilize the disordered native state of the Alzheimer's Aβ peptide and disrupt the binding of mHtt to a cell target provide hints of feasibility of this approach. 61,62 ■ METHODS Cell Culture. This work used the PC12-derived cell line 14A2.6 with stably integrated DNA of the 103Q Htt Exon1 -EGFP sequences under the control of the inducible VgRxR promoter.…”

Section: ■ Discussionmentioning

confidence: 99%

PolyQ-Expanded Mutant Huntingtin Forms Inclusion Body Following Transient Cold Shock in a Two-Step Aggregation Mechanism

Costa

Mysore

Paruchuri

et al. 2022

ACS Chem. Neurosci.

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Age-dependent formation of insoluble protein aggregates is a hallmark of many neurodegenerative diseases. We are interested in the cell chemistry that drives the aggregation of polyQ-expanded mutant Huntingtin (mHtt) protein into insoluble inclusion bodies (IBs). Using an inducible cell model of Huntington's disease, we show that a transient cold shock (CS) at 4 °C followed by recovery incubation at temperatures of 25−37 °C strongly and rapidly induces the compaction of diffuse polyQexpanded Huntingtin Exon1 -enhanced green fluorescent protein chimera protein (mHtt) into round, micron size, cytosolic IBs. This transient CS-induced mHtt IB formation is independent of microtubule integrity or de novo protein synthesis. The addition of millimolar concentrations of sodium chloride accelerates, whereas urea suppresses this transient CS-induced mHtt IB formation. These results suggest that the low temperature of CS constrains the conformation dynamics of the intrinsically disordered mHtt into labile intermediate structures to facilitate de-solvation and hydrophobic interaction for IB formation at the higher recovery temperature. This work, along with our previous observation of the effects of heat shock protein chaperones and osmolytes in driving mHtt IB formation, underscores the primacy of mHtt structuring and rigidification for H-bond-mediated cross-linking in a two-step mechanism of mHtt IB formation in living cells.

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A Small Molecule Stabilizes the Disordered Native State of the Alzheimer’s Aβ Peptide

Cited by 31 publications

References 64 publications

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity

PolyQ-Expanded Mutant Huntingtin Forms Inclusion Body Following Transient Cold Shock in a Two-Step Aggregation Mechanism

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