SENP-1 Inhibition Alleviates Parkinson's Disease-Related Signs and Reverses Damages from Preformed Fibrils of Alpha-Synuclein
Faculty Mentor Information
Dr. Yong-Hwan Kim, Boise State University
Dr. Dinesh Verma, Boise State University
Presentation Date
7-2025
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the deterioration of both motor and non-motor functions. PD and dementia with Lewy bodies are linked to the misfolding and aggregation of alpha-synuclein, a protein whose normal function remains unclear. Post-translational modifications (PTMs) noticeably alter the normal function and solubility of alpha-synuclein, affecting its roles in normal cellular processes and gain-of-function in pathology. SUMOylation is a PTM where a Small Ubiquitin-like Modifier (SUMO) is covalently attached to proteins, influencing their location, function, and stability. DeSUMOylation carried out by SUMO-specific proteases (SENPs), removes SUMO proteins, which regulates protein solubility and function. Our findings show that SENP1 removes SUMO1 from alpha-synuclein when the preformed fibril (PFF) of alpha-synuclein induced toxicity occurs, implicating reduced SUMOylation in PD pathology. Our results support that SENP1 levels were significantly elevated in the in vitro and in vivo models. A natural SENP1 inhibitor, Momordin Ic reduced the PFF-induced reactive oxygen species (ROS) and protein aggregation in N27p dopaminergic cells. These results suggest that preventing deSUMOylation by SENP1 inhibition can decrease oxidative stress and alpha-synuclein-mediated Lewy body pathology. Therefore, we believe that SENP1 inhibition may offer an excellent therapeutic approach for PD and possibly other neurodegeneration.
SENP-1 Inhibition Alleviates Parkinson's Disease-Related Signs and Reverses Damages from Preformed Fibrils of Alpha-Synuclein
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the deterioration of both motor and non-motor functions. PD and dementia with Lewy bodies are linked to the misfolding and aggregation of alpha-synuclein, a protein whose normal function remains unclear. Post-translational modifications (PTMs) noticeably alter the normal function and solubility of alpha-synuclein, affecting its roles in normal cellular processes and gain-of-function in pathology. SUMOylation is a PTM where a Small Ubiquitin-like Modifier (SUMO) is covalently attached to proteins, influencing their location, function, and stability. DeSUMOylation carried out by SUMO-specific proteases (SENPs), removes SUMO proteins, which regulates protein solubility and function. Our findings show that SENP1 removes SUMO1 from alpha-synuclein when the preformed fibril (PFF) of alpha-synuclein induced toxicity occurs, implicating reduced SUMOylation in PD pathology. Our results support that SENP1 levels were significantly elevated in the in vitro and in vivo models. A natural SENP1 inhibitor, Momordin Ic reduced the PFF-induced reactive oxygen species (ROS) and protein aggregation in N27p dopaminergic cells. These results suggest that preventing deSUMOylation by SENP1 inhibition can decrease oxidative stress and alpha-synuclein-mediated Lewy body pathology. Therefore, we believe that SENP1 inhibition may offer an excellent therapeutic approach for PD and possibly other neurodegeneration.