Genome-wide CRISPR-Cas9 Knockout Screening Reveals a TSPAN3-mediated Endo-lysosome Pathway Regulating the Degradation of α-Synuclein Oligomers

作者：Hu, JunJian; Guan, Xinjie; Zhao, Miao; Xie, Pengqing; Guo, Jifeng; Tan, Jieqiong^*

来源：Molecular Neurobiology, 2023, 60(11): 6731-6747.

DOI：10.1007/s12035-023-03495-5

• & alpha
• -Synuclein
• CRISPR-Cas9
• TSPAN3
• Lysosome
• Degradation

Misfolding and aggregation of a-Synuclein (a-Syn), which are hallmark pathological features of neurodegenerative diseases such as Parkinson's disease (PD) and dementia with Lewy Bodies, continue to be significant areas of research. Among the diverse forms of a-Syn - monomer, oligomer, and fibril, the oligomer is considered the most toxic. However, the mechanisms governing a-Syn oligomerization are not yet fully understood. In this study, we utilized genome-wide CRISPR/Cas9 loss-of-function screening in human HEK293 cells to identify negative regulators of a-Syn oligomerization. We found that tetraspanin 3 (TSPAN3), a presumptive four-pass transmembrane protein, but not its homolog TSPAN7, significantly modulates a-Syn oligomer levels. TSPAN3 was observed to interact with a-Syn oligomers, regulate the amount of a-Syn oligomers on the cell membrane, and promote their degradation via the clathrin-AP2 mediated endo-lysosome pathway. Our findings highlight TSPAN3 as a potential regulator of a-Syn oligomers, presenting a promising target for future PD prevention and treatment strategies.

• 单位
  南方医科大学