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d-Ribose glycates β(2)-microglobulin to form aggregates with high cytotoxicity through a ROS-mediated pathway

Fan-Lou Kong1, Wei Cheng, Jie Chen

  • 1State Key Laboratory of Virology, College of Life Sciences, Wuhan University, China.

Chemico-Biological Interactions
|August 26, 2011
PubMed

Insights

Advanced glycation end products (AGEs) modify beta(2)-microglobulin (β(2)M), forming aggregates linked to hemodialysis-associated amyloidosis (HAA). Ribosylated β(2)M aggregates induce cell death via reactive oxygen species (ROS), highlighting a potential role in HAA pathogenesis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pathology

Background:

  • Beta(2)-microglobulin (β(2)M) modified with advanced glycation end products (AGEs) are key components of amyloid deposits in hemodialysis-associated amyloidosis (HAA).
  • The impact of glycation on β(2)M misfolding and aggregation remains largely uncharacterized.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the formation of aggregates from ribosylated β(2)M, a form relevant to HAA.
  • To assess the cytotoxicity and cellular pathways involved in the aggregation of glycated β(2)M.

Main Methods:

  • In vitro incubation of human β(2)M with the glycating agent d-ribose to form AGEs.
  • Characterization of aggregate morphology and oligomerization state.
  • Assessment of cytotoxicity in human neuroblastoma (SH-SY5Y) and fibroblast (FS2) cell lines.
  • Measurement of intracellular reactive oxygen species (ROS) production and the effect of N-acetylcysteine.

Main Results:

  • D-ribose modification of β(2)M generates AGEs that form granular aggregates in a time-dependent manner.
  • Ribosylated β(2)M exhibits higher oligomerization and significant cytotoxicity compared to unglycated β(2)M.
  • These aggregates induce intracellular ROS, and their cytotoxicity is attenuated by the antioxidant N-acetylcysteine, indicating a ROS-mediated pathway.

Conclusions:

  • Ribosylated β(2)M forms granular aggregates with high cytotoxicity through a ROS-mediated pathway.
  • These findings suggest that ribosylated β(2)M aggregates contribute to cellular dysfunction and death.
  • The study highlights the potential role of ribosylated β(2)M aggregates in the pathogenesis of β(2)M-associated diseases like HAA.

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