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

May, Verena E.L.; Nuber, Silke; Marxreiter, Franz; Rieß, Olaf; Winner, Beate; Winkler, Jürgen

doi:10.1016/j.neuroscience.2012.07.001

Cited by 16 publications

(15 citation statements)

References 56 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We previously demonstrated that overexpression of human mutant α-syn reduced DA level and TH immunoreactivity [71]. Additionally, its constant high expression levels due to its overexpression via an artificial promoter may hinder a compensatory genesis of new DAergic olfactory neurons [56, 59]. This is in line with previous studies, suggesting an inverse correlation of α-syn overexpression on DAergic function [14, 68, 75, 99].…”

Section: Discussionsupporting

confidence: 76%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 76%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…A subsequent study using mice overexpressing human SNCA under the tet-off system investigated if impaired OB Neural stem cells in PD 777 neurogenesis caused by SNCA overexpression could be rescued when the transgene is silenced [170]. As in the case of Winner et al, the authors demonstrated a decrease in NSC proliferation in the SVZ and in the generation of new neurons in the OB.…”

Section: Snca (Park1/park4)mentioning

confidence: 97%

“…On the other hand, glomerular layer neurogenesis was partially restored. It is worth mentioning that the amount of newly TH-positive cells was also reduced when the transgene was active and upon its silencing, the number of TH-positive cells was increased up to 89 % in the glomerular layer of the bulb [170].…”

Section: Snca (Park1/park4)mentioning

confidence: 99%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

show abstract

“…A detrimental impact of human α-syn on adult neurogenesis has been reported in mouse models expressing wild-type (WT) and mutant (A53T, A30P) α-syn (Winner et al, 2004, 2008, 2012). Importantly, in conditional mouse models, the suppression of either WT or A30P expression is able to restore the negative influence of α-syn on neurogenesis related to the olfactory bulb (Marxreiter et al, 2009; May et al, 2012; Song et al, 2002). The functional role of hippocampal neurogenesis is matter of intensive debate, e.g.…”

Section: Introductionmentioning

confidence: 99%

Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice

Marxreiter

Ettle

May

et al. 2013

Neurobiology of Disease

View full text Add to dashboard Cite

In Parkinson’s disease (PD) patients, alpha-synuclein (α-syn) pathology advances in form of Lewy bodies and Lewy neurites throughout the brain. Clinically, PD is defined by motor symptoms that are predominantly attributed to the dopaminergic cell loss in the substantia nigra. However, motor deficits are frequently preceded by smell deficiency or neuropsychological symptoms, including increased anxiety and cognitive dysfunction. Accumulating evidence indicates that aggregation of α-syn impairs synaptic function and neurogenic capacity that may be associated with deficits in memory, learning and mood. Whether and how α-syn accumulation contributes to neuropathological events defining these earliest signs of PD is presently poorly understood. We used a tetracycline-suppressive (tet-off) transgenic mouse model that restricts overexpression of human A30P α-syn to neurons owing to usage of the neuron-specific CaMKIIα promoter. Abnormal accumulation of A30P correlated with a decreased survival of newly generated neurons in the hippocampus and olfactory bulb. Furthermore, when A30P α-syn expression was suppressed, we observed reduction of the human protein in neuronal soma. However, residual dox resistant A30P α-syn was detected in glial cells within the hippocampal neurogenic niche, concomitant with the failure to fully restore hippocampal neurogenesis. This finding is indicative to a potential spread of pathology from neuron to glia. In addition, mice expressing A30P α-syn show increased anxiety-related behavior that was reversed after dox treatment. This implies that glial A30P α-synucleinopathy within the dentate gyrus is part of a process leading to impaired hippocampal neuroplasticity, which is, however, not a sole critical event for circuits implicated in anxiety-related behavior.

show abstract

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

Cited by 16 publications

References 56 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

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice

Contact Info

Product

Resources

About