A30P α-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network

Neuner, Johanna; Filser, Severin; Michalakis, Stylianos; Biel, Martin; Herms, Jochen

doi:10.1038/srep03931

Cited by 18 publications

(19 citation statements)

References 61 publications

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“…OB neurogenesis was also examined in the latter experiment but no difference in the number of newly generated neurons in the OB, based on BrdU labeling assays, was detected. Instead, it is likely that the olfaction deficits observed in SNCA transgenic mice are due, at least in part, to impaired growth and branching of dendrites and the subsequent failed stable integration into the OB of newly born DA neurons during adult neurogenesis, leading to a decrease in cell survival, as has been described for an A30P SNCA overexpressing mouse [182,183].…”

Section: Snca (Park1/park4)mentioning

confidence: 97%

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.

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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.

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Section: Snca (Park1/park4)mentioning

confidence: 97%

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.

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“…Regarding the translation of preclinical data to clinical practise, impairment of olfaction may precede Parkinson’s disease in otherwise asymptomatic olfactory function [ 122 , 123 ]. An experimental model of Parkinson’s disease revealed a decrease of the odor discrimination and concominant reduction of neurogenesis [ 124 ]. The purpose of the upcoming preclinical study is enhancement of neurogenesis in the senescent or neurodegenerative brain and recovery of brain functions [ 125 , 126 ].…”

Section: Radiation-induced Changesmentioning

confidence: 99%

Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review

Bálentová

Adamkov

2015

IJMS

129

105

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Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors.

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“…Previous studies in our lab and others have indicated that olfactory dysfunction, which is a non-motor symptom of PD that can precede onset of motor symptoms by many years, is inherent in experimental models of PD and Mn neurotoxicity (Dranka et al, 2014; Neuner et al, 2014; Ngwa et al, 2014; Zhang et al, 2015). We therefore performed a social discrimination test to examine the effects of Mn exposure on olfaction.…”

Section: Resultsmentioning

confidence: 94%

“…Anxiolytic and depressive phenotyping were outside the scope of this paper, but would provide valuable insight and should be explored in future studies. In terms of non-motor deficits, olfactory deficits found in Mn-treated mice during this study (Figure 1H) could potentially be due to increased protein aggregation, reductions in neurogenesis, or changes in the olfactory epithelium or receptors (Chiu et al, 2015; Kurtenbach et al, 2013; Neuner et al, 2014; Postuma and Berg, 2016).…”

Section: Discussionmentioning

confidence: 95%

Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson’s disease: Relevance to gene and environment interactions in metal neurotoxicity

Langley

Ghaisas

et al. 2018

NeuroToxicology

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Parkinson's disease (PD) is now recognized as a neurodegenerative condition caused by a complex interplay of genetic and environmental influences. Chronic manganese (Mn) exposure has been implicated in the development of PD. Since mitochondrial dysfunction is associated with PD pathology as well as Mn neurotoxicity, we investigated whether Mn exposure augments mitochondrial dysfunction and neurodegeneration in the nigrostriatal dopaminergic system using a newly available mitochondrially defective transgenic mouse model of PD, the MitoPark mouse. This unique PD model recapitulates key features of the disease including progressive neurobehavioral changes and neuronal degeneration. We exposed MitoPark mice to a low dose of Mn (10mg/kg, p.o.) daily for 4 weeks starting at age 8 wks and then determined the behavioral, neurochemical and histological changes. Mn exposure accelerated the rate of progression of motor deficits in MitoPark mice when compared to the untreated MitoPark group. Mn also worsened olfactory function in this model. Most importantly, Mn exposure intensified the depletion of striatal dopamine and nigral TH neuronal loss in MitoPark mice. The neurodegenerative changes were accompanied by enhanced oxidative damage in the striatum and substantia nigra (SN) of MitoPark mice treated with Mn. Furthermore, Mn-treated MitoPark mice had significantly more oligomeric protein and IBA-1-immunoreactive microglia cells, suggesting Mn augments neuroinflammatory processes in the nigrostriatal pathway. To further confirm the direct effect of Mn on impaired mitochondrial function, we also generated a mitochondrially defective dopaminergic cell model by knocking out the TFAM transcription factor by using a CRISPR-Cas9 gene-editing method. Seahorse mitochondrial bioenergetic analysis revealed that Mn decreases mitochondrial basal and ATP-linked respiration in the TFAM KO cells. Collectively, our results reveal that Mn can augment mitochondrial dysfunction to exacerbate nigrostriatal neurodegeneration and PD-related behavioral symptoms. Our study also demonstrates that the MitoPark mouse is an excellent model to study the gene-environment interactions associated with mitochondrial defects in the nigral dopaminergic system as well as to evaluate the contribution of potential environmental toxicant interactions in a slowly progressive model of Parkinsonism.

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A30P α-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network

Cited by 18 publications

References 61 publications

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

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

Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review

Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson’s disease: Relevance to gene and environment interactions in metal neurotoxicity

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