Inflammatory and Cell Death Pathways in Brain and Peripheral Blood in Parkinson’s Disease

Author(s): Beatrice Macchi, Rosanna Di Paola, Francesca Marino-Merlo, Maria Rosa Felice, Salvatore Cuzzocrea, Antonio Mastino.

Journal Name: CNS & Neurological Disorders - Drug Targets

Volume 14 , Issue 3 , 2015

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Abstract:

Evidence has been accumulated showing that inflammatory and cell death pathways are altered both in brain and periphery during Parkinson disease (PD). Neuronal loss in PD is associated with chronic neuroinflammation characterized by microglia activation through the release of reactive oxygen radicals, cytokines, and Prostaglandin E2. The release of these inflammatory mediators in addition to deprivation in growth factors and increase of calcium and dopamine seem implicated in triggering apoptosis. The interaction of leucine-rich repeat kinase and Fas- Associated protein with Death Domain has been implicated in the switching-on of the extrinsic apoptotic pathway via caspase-8 activation, while deficiency in PTEN induced putative kinase 1 has been shown to cause Ca2+ accumulation in mitochondria, increased generation of reactive oxygen species and intrinsic cell death. Autophagy/mitophagy appears to be impaired in the brain during PD; this impairment could be related to defective degradation of mutant α-synuclein and consequent apoptotic cell death. Regarding the peripheral blood, reduced amounts of dopamine, reduced levels of immunoreactivity for tyrosine hydroxylase and dopamine active transporter, and alterations of dopamine receptor expression have been detected in mononuclear cells from PD patients. In addition, mononuclear cells from PD patients show mitochondrial, ubiquitin–proteasome system dysfunction and up-regulation of α-synuclein gene, associated to high expression of the Fas molecule, activation of caspase-3 and -9 and proneness to apoptosis. These and other observations reported in this mini-review suggest that a better understanding of molecular dysfunctions in inflammatory and cell death/autophagy pathways, both in the brain and peripheral blood, could provide useful targets for future investigation on drug-discovery and biomarker identification in PD.

Keywords: Apoptosis, autophagy, inflammation, oxidative stress, Parkinson’s disease, target-therapy.

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Article Details

VOLUME: 14
ISSUE: 3
Year: 2015
Page: [313 - 324]
Pages: 12
DOI: 10.2174/1871527314666150225124928
Price: $58

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