Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain

Chauhan, Neelima B.; Siegel, George J.; Lee, John M.

doi:10.1016/s0891-0618(01)00115-6

Cited by 195 publications

(133 citation statements)

References 40 publications

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“…To our knowledge, this is the first report showing modulation of HO-1 by GDNF, with potential relevance to PD. The lower levels of GDNF reported in the substantia nigra of PD patients [67] may contribute to the increased HO-1 levels observed in this brain region, where a significant increase in the fraction of astrocytes expressing HO-1 has been reported and neurons exhibit intense HO-1 immunostaining in the periphery of the Lewy bodies ([13], reviewed in [5]). The upregulation of HO-1 in response to conditions of oxidative stress would then become overwhelming, and the release of iron from heme degradation by HO-1 would exacerbate oxidative injury to dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 99%

GDNF modulates HO-1 expression in substantia nigra postnatal cell cultures

Saavedra

Baltazar

Carvalho

et al. 2005

Free Radical Biology and Medicine

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Heme oxygenase-1 (HO-1) has been strongly highlighted because of its induction in many cell types by toxic stimuli, including oxidative stress. The intense HO-1 immunostaining in the substantia nigra of Parkinson disease (PD) patients suggests its involvement in the pathogenesis of this neurodegenerative disease. In this work we investigated HO-1 expression in rat substantia nigra postnatal cell cultures under conditions mimicking dopamine toxicity and its modulation by glial cell line-derived neurotrophic factor (GDNF), a potent neuroprotective factor for dopaminergic neurons. In neuron -glia cultures, we found that H 2 O 2 , a product of dopamine metabolism, or l-3,4-dihydroxyphenylalanine (l-DOPA), the dopamine precursor used in the therapy of PD, induced a fast up-regulation of HO-1 mRNA and protein levels, followed by a secondary down-regulation. H 2 O 2 and l-DOPA also increased HO-1 expression in astrocyte cultures, but with a delayed time course in H 2 O 2 -treated cultures. HO-1 expression was decreased in neuron -glia cultures under conditions under which GDNF up-regulation was observed. Because exogenously applied GDNF prevented HO-1 up-regulation in cultures treated with H 2 O 2 or l-DOPA, and antibody neutralization of GDNF prevented the secondary HO-1 down-regulation observed in neuron -glia cultures, we propose that GDNF negatively modulates HO-1 expression induced by oxidative stress. To our knowledge, this is the first report showing the modulation of HO-1 expression by GDNF. D

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Section: Discussionmentioning

confidence: 99%

GDNF modulates HO-1 expression in substantia nigra postnatal cell cultures

Saavedra

Baltazar

Carvalho

et al. 2005

Free Radical Biology and Medicine

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“…Both BDNF and TrkB are expressed by DA neurons (Okazawa et al, 1992;Nishio et al, 1998;Numan and Seroogy, 1999;Venero et al, 2000). Postmortem studies of PD patients using in situ hybridization, immunohistochemistry, and Western blot analysis demonstrate that reduced levels of BDNF within the SNC accompany the disease condition (Mogi et al, 1999;Parain et al, 1999;Howells et al, 2000;Chauhan et al, 2001). In culture experiments, BDNF has been found to promote the survival and differentiation of mesencephalic DA neurons (Hyman et al, 1991;Feng et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Is Required for the Establishment of the Proper Number of Dopaminergic Neurons in the Substantia Nigra Pars Compacta

Baquet¹,

Bickford²,

Jones³

2005

J. Neurosci.

270

190

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Brain-derived neurotrophic factor (BDNF) has been implicated in regulating neuronal survival, differentiation, and synaptic plasticity. Reduced expression of BDNF within the substantia nigra accompanies the deterioration of dopaminergic neurons in Parkinson's disease (PD) patients. Analysis of the effects of long-term BDNF absence from the CNS has been difficult because of the early postnatal lethality of BDNF Ϫ/Ϫ mice. Mice with a floxed BDNF allele were bred with Wnt1-Cre mice to generate Wnt-BDNF KO mice that lack BDNF from the midbrain-hindbrain (MHB). These mice are viable but exhibit hindlimb clutching and poor rotarod performance. Tyrosine hydroxylase (TH)-positive neuron numbers in the substantia nigra pars compacta (SNC) were estimated using stereological methods, revealing a persistent ϳ23% reduction of these cells at postnatal day 21 (P21) in Wnt-BDNF KO mice compared with controls. The diminishment of TH-expressing neurons was present at birth and continued through P120. This deficit appears selective for the dopaminergic population, because at P21, total neuron number within the SNC, defined as neuronal nuclei protein-positive cells, was not significantly reduced. Interestingly, and similar to observations in PD patients, SNC neuron subpopulations are not equally affected. Calbindin-and calretininexpressing SNC populations show no significant difference between Wnt-BDNF KO mice and controls. Thus, BDNF depletion from the MHB selectively leads to reduced TH expression in a subpopulation of neurons, but it remains unclear whether these cells are lost.

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“…Disturbances in the energy balance prime these neurons for an early cell death [ 108 ]. Moreover, the proportion of glia, and their resulting metabolic support, within affected regions of dopamine synthesis is lower compared to other brain areas [ 109 ]. Another factor of dopaminergic degeneration may be the intracellular spreading of misfolded α-synuclein protein [ 110 , 111 ].…”

Section: Componentsmentioning

confidence: 99%

Neurological Diseases from a Systems Medicine Point of View

Ostaszewski

Skupin

Balling

2016

Methods in Molecular Biology

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The diffi culty to understand, diagnose, and treat neurological disorders stems from the great complexity of the central nervous system on different levels of physiological granularity. The individual components, their interactions, and dynamics involved in brain development and function can be represented as molecular, cellular, or functional networks, where diseases are perturbations of networks. These networks can become a useful research tool in investigating neurological disorders if they are properly tailored to refl ect corresponding mechanisms. Here, we review approaches to construct networks specifi c for neurological disorders describing disease-related pathology on different scales: the molecular, cellular, and brain level. We also briefl y discuss cross-scale network analysis as a necessary integrator of these scales.

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Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain

Cited by 195 publications

References 40 publications

GDNF modulates HO-1 expression in substantia nigra postnatal cell cultures

GDNF modulates HO-1 expression in substantia nigra postnatal cell cultures

Brain-Derived Neurotrophic Factor Is Required for the Establishment of the Proper Number of Dopaminergic Neurons in the Substantia Nigra Pars Compacta

Neurological Diseases from a Systems Medicine Point of View

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