Midbrain neuronal cultures from parkin mutant mice are resistant to nitric oxide-induced toxicity

Solano, Rosa M.; Menéndez, Jaime; Casarejos, Marı́a José; Rodríguez-Navarro, José Antonio; Yébenes, Justo Garcı́a de; Mena, María A.

doi:10.1016/j.neuropharm.2006.03.027

Cited by 19 publications

(23 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings support the relation of CMA with oxidative stress [66]. GSH homeostasis is critical for the survival of parkin null cultures and their resistance to several neurotoxins [36,49,67]. On the other hand, GSH may be neuroprotective for parkin null neurons via scavenging free radicals and facilitating CMA [49].…”

Section: Discussionsupporting

confidence: 74%

Parkin Null Cortical Neuronal/Glial Cultures are Resistant to Amyloid-β1-42 Toxicity: A Role for Autophagy?

Solano

Casarejos

Gómez

et al. 2012

JAD

View full text Add to dashboard Cite

Abstract. Dementia occurs often in late stages of Parkinson's disease (PD) but its cause is unknown. Likewise there is little information about the interaction between proteins that produce PD and those implicated in Alzheimer's disease (AD). Here we have investigated the interactions between parkin protein and the amyloid-␤ (A␤) 1-42 peptide. We examined the effects of oligomeric A␤ 1-42 peptide on the survival, differentiation, and signaling pathways in cortical cultures from wild type (WT) and parkin null (PK-KO) mice. We discovered that PK-KO cells were more resistant than WT to A␤ 1-42 . This peptide induced neuronal cell death, astrogliosis, microglial proliferation, and increased total and hyperphosphorylated tau and levels of chaperones HSP-70 and CHIP in WT, but not in A␤-treated PK-KO cultures. A␤ 1-42 decreased proteasome activities in WT and PK-KO cultures, but the ubiquitination of proteins only increased in WT cultures. A␤ 1-42 induced a short activation of ERK1/2 and AKT signaling pathways, implicated in cell survival, in PK-KO-treated cells, and a shift in the autophagy marker LC3-II/LC3-I ratio. In addition, the percentage of cells immunoreactive to both HSC70 and LAMP-2A increased in PK-KO cultures versus WT and furthermore in PK-KO cultures treated with A␤ 1-42 . Pre-treatment with inhibitors of glutathione synthesis or autophagy reverted the resistance to A␤ 1-42 of the PK-KO cultures. In conclusion, the loss of parkin protein triggers the compensatory mechanisms of cell protection against A␤ . Parkin suppression, therefore, is not a risk factor for dementia of AD type.

show abstract

Section: Discussionsupporting

confidence: 74%

Parkin Null Cortical Neuronal/Glial Cultures are Resistant to Amyloid-β1-42 Toxicity: A Role for Autophagy?

Solano

Casarejos

Gómez

et al. 2012

JAD

View full text Add to dashboard Cite

show abstract

“…Midbrain neuronal cultures from PK-KO mice are resistant to L-3,4-dihydroxyphenylalanine and NO-induced toxicity, but this resistance disappears when GSH synthesis is inhibited by BSO Solano et al, 2006), which switches the effects of catecholamines from neuroprotective to neurotoxic. GPx and GSH protect mouse astrocytes from iron-mediated H 2 O 2 toxicity (Liddell et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…BSO reduced the normally high content of GSH of both PK-KO and WT cultures Solano et al, 2006). Treatment with 3AT for 2 h completely inhibited catalase activity (Dringen and Hamprecht, 1997).…”

Section: Parkin Null Glial Cultures Are More Resistant To Hydrogen Pementioning

confidence: 93%

Glial Dysfunction in Parkin Null Mice: Effects of Aging

Solano¹,

Casarejos²,

et al. 2008

View full text Add to dashboard Cite

Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals, and abnormal neurotransmitter release. The role of glia in parkin deficiency is little known. We cultured midbrain glia from wild-type (WT) and parkin knock-out (PK-KO) mice. After 18 -20 d in vitro, PK-KO glial cultures had less astrocytes, more microglia, reduced proliferation, and increased proapoptotic protein expression.PK-KO glia had greater levels of intracellular glutathione (GSH), increased mRNA expression of the GSH-synthesizing enzyme ␥-glutamylcysteine synthetase, and greater glutathione S-transferase and lower glutathione peroxidase activities than WT. The reverse happened in glia cultured in serum-free defined medium (EF12) or in old cultures. PK-KO glia was more susceptible than WT to transference to EF12 or neurotoxins (1-methyl-4-phenylpyridinium, blockers of GSH synthesis or catalase, inhibitors of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3 kinases), aging of the culture, or combination of these insults. PK-KO glia was less susceptible than WT to Fe 2ϩ plus H 2 O 2 and less responsive to protection by deferoxamine. Old WT glia increased the expression of heat shock protein 70, but PK-KO did not. Glia conditioned medium (GCM) from PK-KO was less neuroprotective and had lower levels of GSH than WT. GCM from WT increased the levels of dopamine markers in midbrain neuronal cultures transferred to EF12 more efficiently than GCM from PK-KO, and the difference was corrected by supplementation with GSH. PK-KO-GCM was a less powerful suppressor of apoptosis and microglia in neuronal cultures. Our data prove that abnormal glial function is critical in parkin mutations, and its role increases with aging.

show abstract

“…We have investigated the effects of NO-donating agents on midbrain neuronal cultures from PK-KO mice [133]. PK-KO cultures were more resistant than WT to the neurotoxicity by NO, and the difference of susceptibility applied equally to DAergic, GABAergic and the total number of neurons, as well as to astrocytes.…”

Section: Genes and Endogenous Free Radical Do-norsmentioning

confidence: 99%

On the Pathogenesis and Neuroprotective Treatment of Parkinson Disease: What have we Learned from the Genetic Forms of this Disease?

Mena¹,

Rodríguez-Navarro

Ros³

et al. 2008

CMC

View full text Add to dashboard Cite

Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 3 million patients in Europe and North America, characterized by a core phenotype of motor deficits, akinesia, rigidity, postural disturbance and tremor, which is complicated by other neurological deficits during its long progression. Our knowledge about the pathophisiology of PD was limited, up to 25 years ago, to the observation of the lesion of the nigro-striatal dopamine neurons in these patients. The subjects who developed PD as a consequence of exposure to neurotoxic compounds, increased our knowledge about the pathogenesis of this disease. More recently, genetic alterations have been found in patients with PD. The function of the proteins coded by the genes involved in PD has been investigated in genetic models of this disease from invertebrate to rodents. Mutated proteins responsible for PD have been tested in vivo and in vitro, in cellular models or in artificial constructs. A wealth of important information about the function of alpha-synuclein, parkin, DJ-1, PINK and dardarin is available, most notably about the first two causes of familial PD discovered, alpha-synuclein and parkin, responsible for autosomal dominant and autosomal recessive PD, respectively. Different animal models of alpha-synuclein and parkin have been extensively investigated. The in vitro and in vivo studies performed in genetic models of PD have shown that the proteins involved in the pathogenesis of PD interact with one another and have multiple mechanisms of cell toxicity. From the available data, it is clear that the mechanisms leading to cell degeneration in PD are variable in the different subtypes of this disease. Neuroprotective therapies should, therefore, be multiple and tailored according to the factors involved in the different cases. In this study, we review what we have learned from the genetic models of PD and the putative strategies to be tested in the near future.

show abstract

Midbrain neuronal cultures from parkin mutant mice are resistant to nitric oxide-induced toxicity

Cited by 19 publications

References 89 publications

Parkin Null Cortical Neuronal/Glial Cultures are Resistant to Amyloid-β1-42 Toxicity: A Role for Autophagy?

Parkin Null Cortical Neuronal/Glial Cultures are Resistant to Amyloid-β1-42 Toxicity: A Role for Autophagy?

Glial Dysfunction in Parkin Null Mice: Effects of Aging

On the Pathogenesis and Neuroprotective Treatment of Parkinson Disease: What have we Learned from the Genetic Forms of this Disease?

Contact Info

Product

Resources

About