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Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
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Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
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Huntington Disease l: Introduction01:21

Huntington Disease l: Introduction

Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...
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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
07:08

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Published on: February 27, 2018

Kinetically competing huntingtin aggregation pathways control amyloid polymorphism and properties.

Murali Jayaraman1, Rakesh Mishra, Ravindra Kodali

  • 1Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, United States.

Biochemistry
|March 22, 2012
PubMed
Summary

Huntington's disease protein aggregation is driven by the huntingtin N-terminal (httNT) segment. Inhibitors targeting httNT block one pathway, allowing another to dominate, revealing competing amyloid nucleation mechanisms.

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Area of Science:

  • Neurodegenerative diseases
  • Protein misfolding and aggregation
  • Molecular mechanisms of disease

Background:

  • Polyglutamine (polyQ) expansion in huntingtin (htt) causes Huntington's disease.
  • The htt N-terminal (httNT) segment drives polyQ aggregation by concentrating polyQ segments.
  • Aggregation inhibitors aim to disrupt httNT-mediated concentration.

Purpose of the Study:

  • Characterize the nature and limits of httNT-mediated aggregation inhibition.
  • Investigate the interplay between different amyloid nucleation pathways.
  • Understand how inhibitors affect htt aggregation mechanisms.

Main Methods:

  • Studied htt fragments with polyQ expansions.
  • Assessed inhibition by httNT peptides, proteolysis/mutagenesis, and an immunoglobulin-based inhibitor (antihttNT V(L) 12.3).
  • Analyzed the kinetics of amyloid nucleation pathways.

Main Results:

  • httNT peptide inhibitors and httNT removal block only the httNT-mediated pathway.
  • An alternative nucleation pathway dominates when the httNT pathway is inhibited.
  • The antihttNT V(L) 12.3 protein inhibits both httNT-dependent and -independent pathways, yielding nonamyloid oligomers.
  • Identified direct kinetic competition between httNT-dependent and -independent amyloid nucleation pathways.

Conclusions:

  • Amyloid formation in htt fragments involves distinct, competing nucleation pathways.
  • Inhibitor efficacy depends on targeting specific pathways.
  • Amyloid polymorphism is influenced by assembly mechanisms and kinetics.
  • Intracellular environment can modulate htt aggregation pathways.