GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

Abstract

α‐Synuclein is a key player in the pathogenesis of Parkinson disease (PD). Expression of human heme oxygenase‐1 (HO‐1) in astrocytes of GFAP.HMOX1 transgenic (TG) mice between 8.5 and 19 months of age results in a parkinsonian phenotype characterized by neural oxidative stress, nigrostriatal hypodopaminergia associated with locomotor incoordination, and overproduction of α‐synuclein. We identified two microRNAs (miR‐), miR‐153 and miR‐223, that negatively regulate α‐synuclein in the basal ganglia of male and female GFAP.HMOX1 mice. Serum concentrations of both miRNAs progressively declined in the wild‐type (WT) and GFAP.HMOX1 mice between 11 and 19 months of age. Moreover, at each time point surveyed, circulating levels of miR‐153 were significantly lower in the TG animals compared to WT controls, while α‐synuclein protein concentrations were elevated in erythrocytes of the GFAP.HMOX1 mice at 19 months of age relative to WT values. Primary WT neurons co‐cultured with GFAP.HMOX1 astrocytes exhibited enhanced protein oxidation, mitophagy and apoptosis, aberrant expression of genes regulating the dopaminergic phenotype, and an imbalance in gene expression profiles governing mitochondrial fission and fusion. Many, but not all, of these neuronal abnormalities were abrogated by small interfering RNA (siRNA) knockdown of α‐synuclein, implicating α‐synuclein as a potent, albeit partial, mediator of HO‐1's neurodystrophic effects in these parkinsonian mice. Overexpression of HO‐1 in stressed astroglia has previously been documented in the substantia nigra of idiopathic PD and may promote α‐synuclein production and toxicity by downmodulating miR‐153 and/or miR‐223 both within the CNS and in peripheral tissues.

Salivary microR‐153 and microR‐223 Levels as Potential Diagnostic Biomarkers of Idiopathic Parkinson's Disease

“…Although miR‐7 has been linked to α‐synuclein, we did not observe significant alterations in miR‐7a or miR‐7b in PD saliva relative to controls. The changes in salivary miRNAs described herein are consistent with our previous findings in the brain and serum of parkinsonian GFAP.HMOX1 mice . Changes in miR‐153 or miR‐223 expression levels did not become more pronounced with disease progression or duration.…”

“…Expression levels of miR‐153, miR‐223 and the gene encoding α‐synuclein, SNCA are highest in midbrain, although they have also been detected in extracellular compartments, including blood, CSF, and saliva, where their levels appear to fluctuate in response to disease state. Several groups, including our own, have linked miR‐153 and, to a lesser extent, miR‐223 to PD pathology . Alterations in miR‐153 levels have been documented in PD CSF and plasma, whereas changes in miR‐223 have been reported in PD serum .…”

“…GFAP.HMOX1 transgenic mice were engineered to overexpress HMOX1 in astrocytes between 8.5 and 19 months of age, recapitulating HO‐1 levels observed in the substantia nigra astrocytes of PD patients . Akin to changes observed in human PD saliva, miR‐153 and miR‐223 were decreased in the serum of GFAP.HMOX1 transgenic mice at multiple time points surveyed relative to age‐matched, wild‐type controls …”

“…MiR‐153 and miR‐223 were selected for further study based on their mRNA target, α‐synuclein, predicted by the TargetScan algorithm and confirmed previously . MiR‐7 was also selected given its purported role in α‐synuclein regulation .…”

“…MiRNAs are short, noncoding RNA species that act in posttranscriptional regulation of messenger RNA (mRNA) by binding the 3’ untranslated region and blocking translation. The overexpression of human HO‐1 in primary astrocytes and parkinsonian GFAP.HMOX1 mice results in altered miRNA profiles when compared with controls . MiR‐153 and miR‐223 were found to regulate α‐synuclein expression in brain downstream of HMOX1 induction .…”