Anti-apoptotic Splicing Variant of AIMP2 Recover Mutant SOD1-Induced Neuronal Cell Death

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Familial amyotrophic lateral sclerosis (ALS) is linked to mutations in superoxide dismutase 1 (SOD1).
• Mutant SOD1 interacts with lysyl-tRNA synthetase (KARS1), but the mechanism of neuronal cell death is unclear.
• Aminoacyl-tRNA synthetase-interacting multi-functional protein 2 (AIMP2) is implicated in cell death pathways.

Purpose of the Study:

• To elucidate the mechanism by which mutant SOD1 and KARS1 interaction leads to neuronal cell death in ALS.
• To investigate the therapeutic potential of AIMP2-DX2, an antagonistic splicing variant of AIMP2, in ALS models.

Main Methods:

• Investigated the interaction between mutant SOD1, KARS1, and AIMP2 in ALS pathogenesis.
• Utilized induced pluripotent stem cell (iPSC)-derived motor neurons and an ALS mouse model.
• Administered AIMP2-DX2 via intrathecal injection of adeno-associated virus (AAV) in mouse models.

Main Results:

• Mutant SOD1 binding to KARS1 releases AIMP2, triggering TRAF2 degradation and TNF-α-induced cell death.
• Overexpression of AIMP2-DX2 suppressed TRAF2 degradation and reduced neuronal cell death in vitro and in vivo.
• DX2 administration improved motor function and survival in a mutant SOD1-ALS mouse model.

Conclusions:

• AIMP2 mediates neuronal cell death downstream of the mutant SOD1-KARS1 interaction in ALS.
• AIMP2-DX2 acts as a therapeutic agent by inhibiting AIMP2-mediated cell death.
• DX2 shows promise for treating ALS by mitigating neuronal inflammation and improving disease outcomes.