Myopathic lamin mutations cause reductive stress and activate the nrf2/keap-1 pathway

Area of Science:

• Cell biology
• Molecular genetics
• Biochemistry

Background:

• Mutations in the LMNA gene cause muscular dystrophy through poorly understood mechanisms.
• LMNA encodes A-type lamins, crucial for nuclear structure and genome organization.
• Understanding how LMNA mutations lead to disease is vital for therapeutic development.

Purpose of the Study:

• To investigate the structural and functional consequences of LMNA missense mutations found in muscular dystrophy patients.
• To elucidate the molecular mechanisms linking mutant lamins to muscle pathology.
• To identify potential therapeutic targets for laminopathies.

Main Methods:

• Structural and functional analysis of LMNA mutations.
• Modeling mutations in Drosophila Lamin C and expressing them in muscle.
• Nuclear stiffness assays, transcription profiling, and biochemical analyses.
• Analysis of patient muscle biopsies.

Main Results:

• Mutations perturbed lamin Ig-fold structure but had minimal impact on nuclear stiffness.
• Cytoplasmic aggregation of lamins and other nuclear envelope proteins occurred.
• Upregulation of Nrf2 target genes was observed, linked to reductive stress and p62/SQSTM1.
• Elevated p62/SQSTM1 and nuclear Nrf2 were confirmed in patient biopsies.

Conclusions:

• LMNA mutations in muscular dystrophy involve subtle lamina alterations and cytoplasmic aggregation.
• A novel link between mutant lamins, reductive stress, p62/SQSTM1, and Nrf2 activation was established.
• These findings suggest therapeutic strategies targeting protein folding, metabolism, and redox homeostasis.