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β2-Microglobulin amyloid fibril-induced membrane disruption is enhanced by endosomal lipids and acidic pH

Sophia C Goodchild1, Tania Sheynis1, Rebecca Thompson1

  • 1Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.

Plos One
|August 8, 2014
PubMed

Insights

Amyloid fibrils of beta2-microglobulin (β2m) disrupt cell membranes, especially in acidic conditions and with specific lipids like BMP. This finding offers insights into dialysis-related amyloidosis (DRA) pathology.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Amyloid protein interactions with cell membranes are implicated in amyloid diseases.
  • Beta2-microglobulin (β2m) fibrils are linked to dialysis-related amyloidosis (DRA) and cause lipid bilayer disruption.
  • The influence of lipid composition and pH on β2m-membrane interactions remains largely unexplored.

Purpose of the Study:

  • To investigate how lipid composition and pH affect membrane damage caused by β2m monomers and fibrils.
  • To elucidate the role of specific anionic lipids, such as bis(monoacylglycero)phosphate (BMP), in β2m-induced membrane disruption.
  • To explore the potential implications of these interactions within the cellular environment, particularly the endocytic pathway.

Main Methods:

  • Liposome preparation with varying anionic lipid compositions.
  • Assays for membrane damage, including dye release and tryptophan fluorescence quenching.
  • Fluorescence confocal microscopy to visualize β2m-lipid interactions.
  • Experiments conducted across a range of pH conditions.

Main Results:

  • Beta2-microglobulin (β2m) fibril-induced membrane disruption is significantly modulated by the anionic lipid composition of the bilayers.
  • Acidic pH enhances the susceptibility of liposomes to damage by β2m fibrils.
  • Maximal membrane disruption occurred with liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH.

Conclusions:

  • The interaction between β2m fibrils and lipid bilayers is dependent on both lipid composition and pH.
  • Acidic conditions, mimicking the endocytic pathway, potentiate β2m fibril-induced membrane damage.
  • These findings suggest a potential role for β2m fibril interactions with endosomal membranes in the osteoarticular tissue destruction observed in dialysis-related amyloidosis (DRA).

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