Neuroreport · 2026
Involvement of 75NTR extracellular domain in rotenone-induced Parkinson's disease cell models.
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You Yifei, Ren Anyan, Wang Nan, Chen Fang, Wang Xianzhi, Li Chen, Wang Hongcai
Аннотация
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.
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.