TY - JOUR
T1 - Baicalein reduces E46K α-synuclein aggregation in vitro and protects cells against E46K α-synuclein toxicity in cell models of familiar Parkinsonism
AU - Jiang, Mali
AU - Porat-Shliom, Yair
AU - Pei, Zhong
AU - Cheng, Yong
AU - Xiang, Lan
AU - Sommers, Katherine
AU - Li, Qing
AU - Gillardon, Frank
AU - Hengerer, Bastian
AU - Berlinicke, Cynthia
AU - Smith, Wanli W.
AU - Zack, Donald J.
AU - Poirier, Michelle A.
AU - Ross, Christopher A.
AU - Duan, Wenzhen
PY - 2010/7
Y1 - 2010/7
N2 - The E46K is a point mutation in α-synuclein (α-syn) that causes familial Parkinsonism with Lewy body dementia. We have now generated a cell model of Parkinsonism/Parkinson's disease (PD) and demonstrated cell toxicity after expression of E46K in the differentiated PC12 cells. E46K α-syn inhibited proteasome activity and induced mitochondrial depolarization in the cell model. Baicalein has been reported to inhibit fibrillation of wild type α-syn in vitro, and to protect neurons against several chemical-induced models of PD. We now report that baicalein significantly attenuated E46K-induced mitochondrial depolarization and proteasome inhibition, and protected cells against E46K-induced toxicity in a cell model of PD. Baicalein also reduced E46K fibrilization in vitro, with a concentration-dependent decrease in beta sheet conformation, though it increased some oligomeric species, and decreased formation of E46K α-syn-induced aggregates and rescued toxicity in N2A cells. Taken together, these data indicate that mitochondrial dysfunction, proteasome inhibition and specific aspects of abnormal E46K aggregation accompany E46K α-syn-induced cell toxicity, and baicalein can protect as well as altering aggregation properties. Baicalein has potential as a tool to understand the relation between different aggregation species and toxicity, and might be a candidate compound for further validation by using in vivoα-syn genetic PD models.
AB - The E46K is a point mutation in α-synuclein (α-syn) that causes familial Parkinsonism with Lewy body dementia. We have now generated a cell model of Parkinsonism/Parkinson's disease (PD) and demonstrated cell toxicity after expression of E46K in the differentiated PC12 cells. E46K α-syn inhibited proteasome activity and induced mitochondrial depolarization in the cell model. Baicalein has been reported to inhibit fibrillation of wild type α-syn in vitro, and to protect neurons against several chemical-induced models of PD. We now report that baicalein significantly attenuated E46K-induced mitochondrial depolarization and proteasome inhibition, and protected cells against E46K-induced toxicity in a cell model of PD. Baicalein also reduced E46K fibrilization in vitro, with a concentration-dependent decrease in beta sheet conformation, though it increased some oligomeric species, and decreased formation of E46K α-syn-induced aggregates and rescued toxicity in N2A cells. Taken together, these data indicate that mitochondrial dysfunction, proteasome inhibition and specific aspects of abnormal E46K aggregation accompany E46K α-syn-induced cell toxicity, and baicalein can protect as well as altering aggregation properties. Baicalein has potential as a tool to understand the relation between different aggregation species and toxicity, and might be a candidate compound for further validation by using in vivoα-syn genetic PD models.
KW - Parkinson's disease
KW - aggregation
KW - baicalein
KW - mitochondria depolarization
KW - proteasome inhibition
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=77953853289&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953853289&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2010.06752.x
DO - 10.1111/j.1471-4159.2010.06752.x
M3 - Article
C2 - 20412383
AN - SCOPUS:77953853289
SN - 0022-3042
VL - 114
SP - 419
EP - 429
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 2
ER -