Glial HMOX1 expression promotes central and peripheral α-synuclein dysregulation and pathogenicity in parkinsonian mice.

Glial HMOX1 expression promotes central and peripheral α-synuclein dysregulation and pathogenicity in parkinsonian mice.

Publication date: Jun 10, 2019

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.

Concepts Keywords
Apoptosis
Astrocytes
Astroglia
Basal Ganglia
Dopaminergic
Erythrocytes
GFAP
Heme
Idiopathic
Locomotor
Mice
MicroRNAs
Mitochondrial Fission
Neurons
Nigrostriatal
Overproduction
Oxidation
Oxidative Stress
Oxygenase
Parkinson
Pathogenesis
Pathogenicity
Phenotype
SiRNA
Substantia Nigra
Toxicity
Transgenic
Wild Type

Semantics

Type Source Name
drug DRUGBANK Dopamine
disease MESH abnormalities
pathway BSID Gene Expression
pathway BSID Apoptosis
pathway BSID Mitophagy
gene UNIPROT MLXIP
gene UNIPROT MYLIP
gene UNIPROT MARCH8
disease MESH incoordination
pathway BSID Oxidative Stress
disease MESH oxidative stress
gene UNIPROT GFAP
disease DOID Parkinson disease
disease MESH Parkinson disease
gene UNIPROT HMOX1

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