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The Journal of Neuroscience, January 16, 2008, 28(3):598-611; doi:10.1523/JNEUROSCI.4609-07.2008

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Neurobiology of Disease
Glial Dysfunction in Parkin Null Mice: Effects of Aging

Rosa M. Solano,¹ Maria J. Casarejos,¹ Jamie Menéndez-Cuervo,¹ Jose A. Rodriguez-Navarro,¹ Justo García de Yébenes,² and Maria A. Mena¹

Departments of ¹Neurobiology and ²Neurology and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Hospital Ramón y Cajal, 28034 Madrid, Spain

Correspondence should be addressed to Dr. Maria A. Mena, Departamento Neurobiología-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, Km 9, Madrid 28034, Spain. Email: maria.a.mena{at}hrc.es

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 Fe²⁺ plus H₂O₂ 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.

Key words: astrocytes; microglia cells; parkin knock-out mice; proliferation index; glutathione; hydrogen peroxide; glia aging; Parkinson's disease

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Received July 5, 2007; revised Nov. 21, 2007; accepted Nov. 29, 2007.

Correspondence should be addressed to Dr. Maria A. Mena, Departamento Neurobiología-Investigación, Hospital Ramón y Cajal, Carretera de Colmenar, Km 9, Madrid 28034, Spain. Email: maria.a.mena{at}hrc.es

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