title: Expression of human E46K-mutated α-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment.
abstract: Parkinson's disease (PD), the second most common neurodegenerative disorder, is etiologically heterogeneous, with most cases thought to arise from a combination of environmental factors and genetic predisposition; about 10% of cases are caused by single gene mutations. While neurotoxin models replicate many of the key behavioral and neurological features, they often have limited relevance to human exposures. Genetic models replicate known disease-causing mutations, but are mostly unsuccessful in reproducing major features of PD. In this study, we created a BAC (bacterial artificial chromosome) transgenic rat model of PD expressing the E46K mutation of α-synuclein, which is pathogenic in humans. The mutant protein was expressed at levels ~2-3-fold above endogenous α-synuclein levels. At 12 months of age, there was no overt damage to the nigrostriatal dopamine system; however, (i) alterations in striatal neurotransmitter metabolism, (ii) accumulation and aggregation of α-synuclein in nigral dopamine neurons, and (iii) evidence of oxidative stress suggest this model replicates several preclinical features of PD. Further, when these animals were exposed to rotenone, a mitochondrial toxin linked to PD, they showed heightened sensitivity, indicating that α-synuclein expression modulates the vulnerability to mitochondrial impairment. We conclude that these animals are well-suited to examination of gene-environment interactions that are relevant to PD.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Cannon
authors.forename: Kindiya D
authors.initials: KD
authors.lastname: Geghman
authors.forename: Victor
authors.initials: V
authors.lastname: Tapias
authors.forename: Thomas
authors.initials: T
authors.lastname: Sew
authors.forename: Michelle K
authors.initials: MK
authors.lastname: Dail
authors.forename: Chenjian
authors.initials: C
authors.lastname: Li
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Greenamyre
mesh_terms: D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D055647:Rats, Transgenic; D012402:Rotenone / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; D012402:Rotenone