Global Proteotoxicity Caused by Human β₂ Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Beta2 microglobulin (β2m) aggregation causes systemic amyloidosis in hemodialysis patients.
• Familial amyloidosis linked to β2m variants like D76N affects visceral organs.
• Understanding β2m toxicity in cellular and organismal environments remains limited.

Purpose of the Study:

• To establish transgenic C. elegans models expressing wild-type (WT) human β2m and amyloidogenic variants (D76N β2m, ΔN6 β2m).
• To investigate the in vivo molecular mechanisms of β2m-associated proteotoxicity and organismal dysfunction.

Main Methods:

• Generation of transgenic C. elegans expressing WT, D76N, and ΔN6 β2m in bodywall muscle.
• Assessment of age-dependent proteotoxicity, motility, development, and lifespan.
• Analysis of endogenous protein aggregation, stress response (heat and ER stress), and protein secretion.

Main Results:

• D76N and ΔN6 β2m variants induced age-dependent proteotoxicity, reduced motility, delayed development, and shortened lifespan in C. elegans.
• Both variants promoted widespread endogenous protein aggregation, exacerbating toxicity in aged animals.
• β2m expression impaired C. elegans' ability to cope with heat and ER stress, with reduced BiP/hsp-4 upregulation.
• Protein secretion was reduced across all β2m variants, suggesting disrupted ER secretory metabolism.

Conclusions:

• Transgenic C. elegans expressing amyloidogenic β2m variants recapitulate key aspects of systemic amyloidosis.
• β2m toxicity is linked to impaired cellular stress responses and disrupted ER secretory function.
• These findings provide a valuable model for studying β2m-related amyloidosis and developing therapeutic strategies.