α-Synuclein–Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons

Decressac, Mickaël; Kadkhodaei, Banafsheh; Mattsson, Bengt; Laguna, Ariadna; Perlmann, Thomas; Björklund, Anders

doi:10.1126/scitranslmed.3004676

Cited by 234 publications

(243 citation statements)

References 65 publications

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“…Although the presence of o-αSyn was not disclaimed in these studies, we advance that these changes might be a result of the presence of αSyn oligomers based on our own in vitro results. Using predictive databases, we found that human and mouse SYN1 and SYN2 promoters contained conserved putative responsive elements for CREB and Nurr1, respectively, two transcription factors involved in αSyn-mediated toxicity (29,30,63). We then found that the protein abundance of pS133-CREB and Nurr1 was decreased in association with the age-dependent accumulation of αSyn oligomers in TgI2.2 mice and following intraneuronal delivery of o-αSyn.…”

Section: Dependence On Endogenous αSyn For Exogenous O-αsyn To Inducementioning

confidence: 96%

“…org), we identified putative responsive elements for cAMP response element binding (CREB) and Nurr1 in the 5′UTR/promoter region of SYN1 and SYN2 (Fig. 5C), two transcription factors known to be suppressed by αSyn (29,30). Importantly, these sequences are conserved between mouse and human genomes.…”

Section: Ic Delivery Of Exogenous O-αsyn Lowers Synapsin Protein Abunmentioning

confidence: 97%

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Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression.α-synuclein | oligomer | memory | Alzheimer's disease | synapsins

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Section: Dependence On Endogenous αSyn For Exogenous O-αsyn To Inducementioning

confidence: 96%

Section: Ic Delivery Of Exogenous O-αsyn Lowers Synapsin Protein Abunmentioning

confidence: 97%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, conditional deletion of Gdnf in adult mice (Gdnf f/f ;Cre-ER TM ) causes mDA neuron loss (Pascual et al, 2008), indicating that GDNF is subsequently required to maintain the survival of mDA neurons. Interestingly, members of the TGFβ family are required for GDNF to exert its effects (Krieglstein et al, 1998), and the expression of the GDNF receptor c-ret (Trupp et al, 1996) is maintained by Nurr1 (Decressac et al, 2012). Moreover, GDNF has been suggested to regulate Bdnf expression via a Gdnf-Pitx3-Bdnf trophic loop (Peng et al, 2011).…”

Section: Differentiation and Survival Of Mda Neuronsmentioning

confidence: 99%

How to make a midbrain dopaminergic neuron

2015

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Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.

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“…A subsequent study showed that α-synuclein overexpression downregulates the expression of Nurr1, and its downstream target, the GDNF receptor Ret (Ref. 87). Further investigation of the cellular mechanisms underlying the neuropathology observed in the AAV-α-syn rat model is warranted, in order to ascertain the validity of this model for future studies on NTFs.…”

Section: ) Lv-gdnf Was Also Shown Viral Vector Delivery Of Neurotrmentioning

confidence: 99%

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

O’Keeffe

Sullivan

2015

Expert Rev. Mol. Med.

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Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

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α-Synuclein–Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons

Abstract: The trophic response of dopamine neurons to GDNF, mediated by the transcription factor Nurr1, protects them from α-synuclein–mediated toxicity.

Cited by 234 publications

References 65 publications

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

How to make a midbrain dopaminergic neuron

Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

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