De novo tetrahydrobiopterin biosynthesis is impaired in the inflammed striatum of parkin(-/-) mice.
Roberta de Paula MartinsViviane GlaserAderbal S AguiarPriscila Maximiliano de Paula FerreiraKarina GhisoniDébora da Luz SchefferLaurence LanfumeyRita Raisman-VozariOlga CortiAna Lucia De PaulRodrigo Augusto da SilvaAlexandra LatiniPublished in: Cell biology international (2018)
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.
Keyphrases
- oxidative stress
- early onset
- inflammatory response
- cell death
- high fat diet induced
- anti inflammatory
- transcription factor
- poor prognosis
- late onset
- ischemia reperfusion injury
- diabetic rats
- induced apoptosis
- mental health
- wild type
- prefrontal cortex
- atomic force microscopy
- metabolic syndrome
- adipose tissue
- magnetic resonance imaging
- stress induced
- signaling pathway
- high resolution
- binding protein
- contrast enhanced
- cell cycle arrest
- high speed