CXCR4 and CXCL12 Expression is Increased in the Nigro-Striatal System of Parkinson’s Disease

Abstract

Except for a handful of inherited cases related to known gene defects, Parkinson's disease (PD) is a sporadic neurodegenerative disease of unknown etiology. There is increasing evidence that inflammation and proliferation of microglia may contribute to the neuronal damage seen in the nigro-striatal dopaminergic system of PD patients. Microglia events that participate in neuronal injury include the release of pro-inflammatory and neurotoxic factors. Characterizing these factors may help to prevent the exacerbation of PD symptoms or to remediate the disease progression. In rodents, the nigro-striatal system exhibits high expression of the chemokine receptor CXCR4. Its natural ligand CXCL12 can promote neuronal apoptosis. Therefore, the present study investigated the expression of CXCR4 and CXCL12 in post-mortem brains of PD and control (non-PD) individuals and in an animal model of PD. In the human substantia nigra (SN), CXCR4 immunoreactivity was high in dopaminergic neurons. Interestingly, the SN of PD subjects exhibited higher expression of CXCR4 expression and CXCL12 than control subjects despite the loss of dopamine (DA) neurons. This effect was accompanied by an increase in activated microglia. However, results from post-mortem brains may not provide indication as to whether CXCL12/CXCR4 can cause the degeneration of DA neurons. To examine the role of these chemokines, we determined the levels of CXCL12 and CXCR4 in the SN of MPTP-treated mice. MPTP produced a time-dependent up-regulation of CXCR4 that preceded the loss of DA neurons. These results suggest that CXCL12/CXCR4 may participate in the etiology of PD and indicate a new possible target molecule for PD.

CXCL12 and CXCR4 in the Peripheral Blood of Patients with Parkinson’s Disease

“…There is a shortage of studies on the role of CXCL12/CXCR4 in the pathogenesis of PD. Our findings are consistent with study by Shimoji et al that assessed the expression of CXCL12/CXCR4 in the substantia nigra of PD patients [25]. The study showed that CXCL12 and CXCR4 are markedly expressed in human subjects with PD.…”

HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis

“…These cytokines are known as main contributors in several neurodegenerative disorders and are typically produced by glia cells, including microglia and astrocytes, as well as neurons. [40][41][42][43] In addition, the vascular growth factor VEGFA, 44 the chemokine receptor CXCR4, [45][46][47] and the multifunctional growth factor TGF␤1, 48,49 were overexpressed in cKO P2/H1 brains, and are related to the initiation and/or secondary phase of neurodegeneration. Interestingly, many of these genes, including EPO, have been described as HIF-2␣-related genes, 25,37 suggesting that loss of HIF-1␣ enhances HIF-2␣ activity, causing brain damage as well as lethality of these mice.…”

Serum Levels of Chemokines in Parkinson’s Disease

“…Increased expression of CXCR4 and CCL12 was detected on the substantia nigra of PD patients [12] . Furthermore, in a murine model of PD, the chemokines CCL2, CCL3, CXCL10 were upregulated in the striatum and the ventral midbrain [13] .…”