Dopaminergic Neuron-Derived AIMP1 Promotes Neurodegeneration via CD23-Dependent Microglial Activation

Parkinson's disease (PD), the second most prevalent age-associated neurodegenerative disorder, is characterized by the degeneration and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SN). Among the intricate pathophysiological processes of PD, chronic neuroinflammation has emerged as a pivotal hallmark in the pathogenesis of PD. The aminoacyl tRNA synthetase complex has been reported to play an important role in modulating the immune response and associated diseases. Nevertheless, the specific functions and implications of the complex in PD remain largely unclear.

Enzyme-linked immunosorbent assay (ELISA) was used to investigate levels of AIMP1 and TNF-α. An in vivo PD model was constructed by administering 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP⁺). Pole test was performed to assess the motor function of mice. DA neuron survival and microglia activation were detected by immunofluorescence. Western blot and qPCR were used to detect the levels of tyrosine hydroxylase (TH) and inflammatory cytokines. RNA-Seq analysis was performed to explore possible mechanisms.

The levels of AIMP1, a co-factor of the aminoacyl tRNA synthetase complex, were significantly elevated in the blood of PD patients. Aimp1 knockout or knockdown remarkably improved the viability of DA neurons in the MPTP-induced mouse model of PD. Aimp1 deficiency reduced microglial activation in PD mice. RNA-Seq analysis revealed that AIMP1 promoted microglial inflammatory response. Moreover, the AIMP1-induced microglial activation was CD23 dependent.

Collectively, our findings indicate that AIMP1 derived from DA neurons exacerbates neuroinflammation, promotes the death of DA neurons and contributes to the development of PD. This study offers novel insights into the molecular mechanisms underlying PD and blocking the AIMP1-CD23 signaling pathway potentially serves as a therapeutic strategy for PD.