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Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

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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.

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Acknowledgments

PD human and control brain samples were supplied by the Parkinson’s UK Tissue Bank, funded by Parkinson’s UK, a charity registered in England and Wales (258197) and Scotland (SC037554), from the tissue bank of the Alzheimer’s Disease Research Center (ADRC) at the University of California at San Diego and analyses done in accordance with the Ethics Committee guidelines. PrP-A30P mice were generated at the University of Tuebingen, Germany. S.N. was awarded with the fellowship of the German Parkinson’s Society. The work was supported by National Institutes of Health grants AG 18440, AG022704, NS057096 and AG5131to E.M, and by NGFNplus 01GS08134 to O.R/S.N.

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  1. Department of Neurosciences, University of California San Diego, 9500 Gilman Dr., MTF 344, La Jolla, CA, 92093-0624, USA

    Silke Nuber, Daniel Tadros, Cassia Rose Overk, Kori Kosberg, Michael Mante, Edward Rockenstein, Margarita Trejo & Eliezer Masliah

  2. Department of Pathology, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0624, USA

    Jerel Fields & Eliezer Masliah

  3. Department of Molecular Neurology, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany

    Benjamin Ettle

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Nuber, S., Tadros, D., Fields, J. et al. Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD. Acta Neuropathol 127, 477–494 (2014). https://doi.org/10.1007/s00401-014-1255-5

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