INSTITUTO DE INVESTIGACIONES EN CIENCIAS DE LA SALUD
Unidad Ejecutora - UE
De novo tetrahydrobiopterin biosynthesis is impaired in the inflammed striatum of parkin(−/−) mice
LATINI, ALEXANDRA; CORTI, OLGA; DA LUZ SCHEFFER, DÉBORA; AGUIAR JR, ADERBAL S.; DA SILVA, RODRIGO AUGUSTO; RAISMAN-VOZARI, RITA; GHISONI, KARINA; GLASER, VIVIANE; DE PAUL, ANA LUCIA; LANFUMEY, LAURENCE; DE PAULA FERREIRA, PRISCILA MAXIMILIANO; DE PAULA MARTINS, ROBERTA
CELL BIOLOGY INTERNATIONAL
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Parkinson´s disease (PD), the second-most prevalent neurodegenerative disease, is primarily characterized by neurodegeneration in the substantia nigra pars compacta, resulting in motor impairment. Loss-of-function mutations in parkin are the major cause of the early onset familial form of the disease. Although rodents deficient in parkin (parkin(-/-)) have some dopaminergic system dysfunction associated with central oxidative stress and energy metabolism deficiencies, these animals only display nigrostriatal pathway degeneration under inflammatory conditions. This study investigated the impact of the inflammatory stimulus induced by lypopolisaccharide (LPS) on tetrahydrobiopterin (BH4) synthesizing enzymes (de novo and salvage pathways), since this cofactor is essential for dopamine synthesis. The mitochondrial content and architecture was investigated in the striatum of LPS-exposed parkin(-/-) mice. As expected, the LPS (0.33 mg/kg; i.p.) challenge compromised spontaneous locomotion and social interaction with juvenile parkin(-/-) and WT mice. Moreover, the genotype impacted the kinetics of the investigation of the juvenile. The inflammatory scenario did not induce apparent changes in mitochondrial ultrastructure; however, it increased the quantity of mitochondria, which were of smaller size, and provoked the perinuclear distribution of the organelle. Furthermore, the BH4 de novo biosynthetic pathway failed to be up-regulated in the LPS challenge, a well-known stimulus for its activation. The LPS treatment increased sepiapterin reductase (SPR) expression, suggesting compensation by the salvage pathway. This might indicate that dopamine synthesis is compromised in parkin(-/-) mice under inflammatory conditions. Finally, this scenario impaired the striatal expression of the transcription factor BDNF, possibly favoring cell death.