Inflammatory Pathways in Parkinson’s Disease; A BNE Microarray Study

Abstract

The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth.

Calcium CaV1 Channel Subtype mRNA Expression in Parkinson’s Disease Examined by In Situ Hybridization

“…The absence of a reduction in the amount of mRNA for Ca V 1 subtype in the substantia nigra and locus coeruleus, where catecholaminergic cell loss occurs in Parkinson's disease, could represent an upregulation of mRNA in the surviving cells in these areas. These data are in keeping with a DNA microarray study from our laboratory which also found no change in Ca V 1.2 or Ca V 1.3 mRNA levels in substantia nigra from patients dying with Parkinson's disease compared to control cases (Durrenberger et al 2012). There is no way of knowing from these experiments whether this presumed increase occurred in surviving dopamine neurons or in other cell types which express Ca V 1 subtypes (e.g.…”

Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease

“…Following these findings, more specifically, the down-regulation of ALDH1A1 mRNA was found by our group using genomewide transcriptomic assay in SN from PD patients compared to controls (Grünblatt et al 2004). Following this report, many other groups could consistently confirm ALDH1A1 down-regulation in the SN of PD patients (Durrenberger et al 2012;Grünblatt 2012;Kotraiah et al 2013). In the last report by Kotraiah et al the analysis was extended to the various splice variants of ALDH1A1, which all showed similar down-regulation (Kotraiah et al 2013).…”

Why is nitric oxide important for our brain?

“…The results of the study by Durrenberger et al (2012) highlighted the roles of eNOS confirming the genetic findings. Thus, increased levels of eNOS-positive cells were found in the substantia nigra of an MPTP mouse model of PD (Durrenberger et al, 2012). Given the dual role of NO, neuroprotective and neurotoxic, it has been pointed out that the interrelation between constitutive forms of NOS and iNOS in cells containing both types of this enzyme (e.g.…”

“…Later genetic studies mapped single nucleotide polymorphisms of NOS genes (NOS1, NOS2A and NOS3) associated with higher production of NO found in PD (Hancock et al, 2008). The results of the study by Durrenberger et al (2012) highlighted the roles of eNOS confirming the genetic findings. Thus, increased levels of eNOS-positive cells were found in the substantia nigra of an MPTP mouse model of PD (Durrenberger et al, 2012).…”