Olfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages

Nuber, Silke; Petrasch‐Parwez, Elisabeth; Arias-Carrión, Óscar; Koch, Leanie; Kohl, Zacharias; Schneider, Jacqueline; Calaminus, Carsten; Dermietzel, Rolf; Самарина, А. В.; Boy, Jana; Nguyen, Huu Phuc; Teismann, Peter; Velavan, Thirumalaisamy P.; Kahle, Philipp J.; Hörsten, Stephan von; Fendt, Markus; Krüger, Rejko; Rieß, Olaf

doi:10.1016/j.nbd.2011.06.017

Cited by 27 publications

(28 citation statements)

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“…We used conditional transgenic mice presenting site-specific and doxycycline-responsive expression of familial PD-linked A30P α-syn in OB neurons, with its strongest expression in olfactory glomerular layer (GL) [71]. In our previous study, overexpression of α-syn reduced olfactory DA levels in absence of olfactory DAergic cell but increased midbrain DA, functionally associating with higher reactivity to novelty stress and aversive odor stimuli in our mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mice with doxycycline (dox, D)-responsive overexpression of human mutant A30P α-syn under conditional control of the prion protein promoter (PrP_A30P; in the present study designated as A30P) were created and previously described [71]. Transgenic A30P ( n = 13) and dox-treated A30P ( n = 13) aged 12 months at the beginning of the experiment were used (see also Fig.…”

Section: Methodsmentioning

confidence: 99%

“…These mice exhibit hyperactivity, and a dysregulation of olfactory and midbrain DAergic circuits in absence of olfactory DAergic cell-death [71]. A similar phenotype was described in young transgenic mice with widespread expression of α-syn [43, 44, 81, 106].…”

Section: Introductionmentioning

confidence: 94%

“…The higher activity towards mild stress was associated with an increase of striatal DAergic marker, eventually normalized and lost at old age [43, 44, 81, 106]. In our previous study, we observed that mice with site-specific α-syn expression in OB neurons develop a similar phenotype and neurochemical changes [71], implying that olfactory circuits may play a role in regulation of the nigrostriatal DAergic tone. Epidemiological studies suggest exposure to environmental toxins as contributing factor to PD pathogenesis that may enter the brain via the olfactory neuroepithelium, laying out the concept of the olfactory vector hypothesis [24, 78].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…The optical density of protein bands was measured by ImageQuant software 5.0 (GE Healthcare, Munich, Germany) as described previously (Nuber et al, 2008(Nuber et al, , 2011. All data were normalized to the expression of b-actin.…”

Section: Western Blot Analysismentioning

confidence: 99%

Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein

May¹,

Nuber²,

Marxreiter³

et al. 2012

Neuroscience

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Olfactory dysfunctions in neurodegenerative disorders

Ruan

Zheng

Zhang

et al. 2012

J of Neuroscience Research

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Olfactory dysfunction is a common symptom in the patients with neurodegenerative disorders, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). Recently, studies of olfactory dysfunction have focused on its potential as a medication-independent biomarker for disease progression and as an early indicator for the diagnosis of neurodegenerative disorders. In the past decades, great achievements have been obtained in elucidating the neuroanatomy and the function of olfactory system, yet the pathogenesis of olfactory dysfunction in neurodegenerative disorders remains elusive. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb, primary olfactory cortices, and their secondary targets changes. This article summarizes the up-to-date knowledge on pathophysiological changes of the olfactory system in neurodegenerative disorders and attempts to find the association between olfactory dysfunction and neurodegenerative disorders.

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Olfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages

Cited by 27 publications

References 87 publications

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

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

Impaired olfactory bulb neurogenesis depends on the presence of human wild-type alpha-synuclein

Olfactory dysfunctions in neurodegenerative disorders

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