Involvement of 75NTR extracellular domain in rotenone-induced Parkinson’s disease cell models

Objective While the p75 neurotrophin receptor (p75NTR) is critically implicated in the aggregation of α-synuclein (α-syn), a defining pathological hallmark of Parkinson’s disease, the distinct functional contributions of its structural domains remain largely unresolved. Methods To investigate this, we employed a rotenone-induced cellular Parkinson’s disease model utilizing SH-SY5Y neuroblastoma cells transfected with plasmids encoding specific p75NTR truncation mutants. Results Overexpression of a mutant representing the p75NTR extracellular domain (HA-p75Δ151, lacking residues 277–427) significantly exacerbated both α-syn expression levels and its aggregation phenotype. This effect is potentially attributable to the aberrant activation of caspase-1. Conversely, unlike full-length p75NTR which enhanced α-syn ubiquitination, the HA-p75Δ151 truncation failed to modulate ubiquitination dynamics. Furthermore, expression of this extracellular domain fragment induced cell cycle dysregulation and promoted cell death. Conclusion These findings delineate the p75NTR extracellular domain-induced α-syn proteotoxic stress. This domain-specific mechanism advances our understanding of Parkinson’s disease pathogenesis and highlights the therapeutic potential of targeting specific p75NTR domains.