title: Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD.
abstract: The olfactory bulb (OB) is one of the first brain regions in Parkinson's disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD.
authors: Department of Neurosciences, University of California San Diego, 9500 Gilman Dr., MTF 344, La Jolla, CA, 92093-0624, USA, snuber@ucsd.edu.
authors: Silke
authors: S
authors: Nuber
authors: Daniel
authors: D
authors: Tadros
authors: Jerel
authors: J
authors: Fields
authors: Cassia Rose
authors: CR
authors: Overk
authors: Benjamin
authors: B
authors: Ettle
authors: Kori
authors: K
authors: Kosberg
authors: Michael
authors: M
authors: Mante
authors: Edward
authors: E
authors: Rockenstein
authors: Margarita
authors: M
authors: Trejo
authors: Eliezer
authors: E
authors: Masliah
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D009830:Olfactory Bulb / Q000187:drug effects / Q000473:pathology*; D010269:Paraquat / Q000633:toxicity; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D009498:Neurotoxins; D051844:alpha-Synuclein; D010269:Paraquat