Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link b...Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.展开更多
Type 2 diabetes mellitus(T2DM)and other metabolic disorders are often silent and go unnoticed in patients because of the lack of suitable prognostic and diagnostic markers.The current therapeutic regimens available fo...Type 2 diabetes mellitus(T2DM)and other metabolic disorders are often silent and go unnoticed in patients because of the lack of suitable prognostic and diagnostic markers.The current therapeutic regimens available for managing T2DM do not reverse diabetes;instead,they delay the progression of diabetes.Their efficacy(in principle)may be significantly improved if implemented at earlier stages.The misfolding and aggregation of human islet amyloid polypeptide(hIAPP)or amylin has been associated with a gradual decrease in pancreatic b-cell function and mass in patients with T2DM.Hence,hIAPP has been recognized as a therapeutic target for managing T2DM.This review summarizes hIAPP's role in mediating dysfunction and apoptosis in pancreatic b-cells via induction of endoplasmic reticulum stress,oxidative stress,mitochondrial dysfunction,inflammatory cytokine secretion,autophagy blockade,etc.Furthermore,it explores the possibility of using intermediates of the hIAPP aggregation pathway as potential drug targets for T2DM management.Finally,the effects of common antidiabetic molecules and repurposed drugs;other hIAPP mimetics and peptides;small organic molecules and natural compounds;nanoparticles,nanobodies,and quantum dots;metals and metal complexes;and chaperones that have demonstrated potential to inhibit and/or reverse hIAPP aggregation and can,therefore,be further developed for managing T2DM have been discussed.展开更多
The conformation change picture of human islet amyloid polypeptide （hlAPP） is outlined using molecular dynamics simulation, and the structural influences of L16Q, S20G, and L16Q-S20G mutations on the conformation of...The conformation change picture of human islet amyloid polypeptide （hlAPP） is outlined using molecular dynamics simulation, and the structural influences of L16Q, S20G, and L16Q-S20G mutations on the conformation of hlAPP are analyzed. Particularly, the conformational changes of the amyloidogenic-related regions of residues 15-- 17 and 20--29 are emphasized. Our studies find that, for WT hlAPP, residues 15--17 always maintain a stable a-helix structure, residues 20--25 structurally fluctuate between turn and 5-helix, and residues 26--29 mainly adopt coil and bend structures. The hydrogen bonds between the polar groups of hlAPP, long-rang van der Waals forces between the residues, and hydrophobic interactions between the residues of hlAPP are important driving forces to maintain the secondary structure of hlAPP. The replacement of leucine 16 by glutamine stabilizes the helix structure of residues 15--17 and 20--23 of hlAPP monomer, and the structure of residues 24--29 fluctuates be- tween helix and turn. The relatively stable helix structures of residues 15--17 and 20--29 are supposed to be beneficial for L16Q hlAPP to resist the aggregation as observed in the experiment. The substitution of serine20 by glycinc drives residues 15--17 and 20--29 of hlAPP to transform from helix structure to β-strands or coil structures with higher extension and flexibility, which may promote the aggregation of hlAPP as the experiments reported. These results are significant to understand the aggregation mechanism of hlAPP monomer into the dimer, trimer, oligomers and fibrils associated with the type 2 diabetes at the atomic level.展开更多
文摘Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.
基金the Wadhwani Research Foundation(Wadhwani Research Centre for Bioengineering,Grant No.:RD/0118-DONWR04-001)Ramalingaswami Fellowship(Project No.:BT/RLF/Re-entry/11/2012,Department of Biotechnology-DBT,Government of India)+4 种基金University Grants Commission(Grant No.:F.4-5(18-FRP)(IV-Cycle)/2017(BSR),Government of India)generously supported by Research and Development Grant to the Department of Biotechnology,SPPU,and UPE Phase Ⅱ and RUSA 2.0 grants to SPPUCSIR-SRF,GOI(Grant No.:(09/137/0602)2019-EMR-I),for her SRF fellowshipWadhwani Research Foundation(Grant No.:RD/0118-DONWR04-001)RUSA 2.0 grants for her project assistant fellowship.
文摘Type 2 diabetes mellitus(T2DM)and other metabolic disorders are often silent and go unnoticed in patients because of the lack of suitable prognostic and diagnostic markers.The current therapeutic regimens available for managing T2DM do not reverse diabetes;instead,they delay the progression of diabetes.Their efficacy(in principle)may be significantly improved if implemented at earlier stages.The misfolding and aggregation of human islet amyloid polypeptide(hIAPP)or amylin has been associated with a gradual decrease in pancreatic b-cell function and mass in patients with T2DM.Hence,hIAPP has been recognized as a therapeutic target for managing T2DM.This review summarizes hIAPP's role in mediating dysfunction and apoptosis in pancreatic b-cells via induction of endoplasmic reticulum stress,oxidative stress,mitochondrial dysfunction,inflammatory cytokine secretion,autophagy blockade,etc.Furthermore,it explores the possibility of using intermediates of the hIAPP aggregation pathway as potential drug targets for T2DM management.Finally,the effects of common antidiabetic molecules and repurposed drugs;other hIAPP mimetics and peptides;small organic molecules and natural compounds;nanoparticles,nanobodies,and quantum dots;metals and metal complexes;and chaperones that have demonstrated potential to inhibit and/or reverse hIAPP aggregation and can,therefore,be further developed for managing T2DM have been discussed.
文摘The conformation change picture of human islet amyloid polypeptide （hlAPP） is outlined using molecular dynamics simulation, and the structural influences of L16Q, S20G, and L16Q-S20G mutations on the conformation of hlAPP are analyzed. Particularly, the conformational changes of the amyloidogenic-related regions of residues 15-- 17 and 20--29 are emphasized. Our studies find that, for WT hlAPP, residues 15--17 always maintain a stable a-helix structure, residues 20--25 structurally fluctuate between turn and 5-helix, and residues 26--29 mainly adopt coil and bend structures. The hydrogen bonds between the polar groups of hlAPP, long-rang van der Waals forces between the residues, and hydrophobic interactions between the residues of hlAPP are important driving forces to maintain the secondary structure of hlAPP. The replacement of leucine 16 by glutamine stabilizes the helix structure of residues 15--17 and 20--23 of hlAPP monomer, and the structure of residues 24--29 fluctuates be- tween helix and turn. The relatively stable helix structures of residues 15--17 and 20--29 are supposed to be beneficial for L16Q hlAPP to resist the aggregation as observed in the experiment. The substitution of serine20 by glycinc drives residues 15--17 and 20--29 of hlAPP to transform from helix structure to β-strands or coil structures with higher extension and flexibility, which may promote the aggregation of hlAPP as the experiments reported. These results are significant to understand the aggregation mechanism of hlAPP monomer into the dimer, trimer, oligomers and fibrils associated with the type 2 diabetes at the atomic level.
