title: Baicalein reduces E46K alpha-synuclein aggregation in vitro and protects cells against E46K alpha-synuclein toxicity in cell models of familiar Parkinsonism.
abstract: The E46K is a point mutation in alpha-synuclein (alpha-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 alpha-syn inhibited proteasome activity and induced mitochondrial depolarization in the cell model. Baicalein has been reported to inhibit fibrillation of wild type alpha-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 alpha-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 alpha-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 vivo alpha-syn genetic PD models.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Mali
authors.initials: M
authors.lastname: Jiang
authors.forename: Yair
authors.initials: Y
authors.lastname: Porat-Shliom
authors.forename: Zhong
authors.initials: Z
authors.lastname: Pei
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.forename: Lan
authors.initials: L
authors.lastname: Xiang
authors.forename: Katherine
authors.initials: K
authors.lastname: Sommers
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Frank
authors.initials: F
authors.lastname: Gillardon
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.forename: Cynthia
authors.initials: C
authors.lastname: Berlinicke
authors.forename: Wanli W
authors.initials: WW
authors.lastname: Smith
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Poirier
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D044950:Flavanones / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors; D051381:Rats; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D044950:Flavanones; D061988:Proteasome Inhibitors; D051844:alpha-Synuclein; C006680:baicalein
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