ABSTRACT
Aggregation of the microtubule-associated protein, tau, can lead to neurofibrillary tangle formation in neurons and glia which is the hallmark of tauopathy. The cellular damage induced by the formation of neurofibrillary tangles leads to neuroinflammation and consecutive neuronal death. However, detailed observation of transcriptomic changes under tauopathy together with the comparison of age-dependent progression of neuroinflammatory gene expressions mediated by tau overexpression is required. Employing RNA sequencing on PS19 transgenic mice that overexpress human mutant tau harboring the P301S mutation, we have examined the effects of age-dependent tau overexpression on transcriptomic changes of immune and inflammatory responses in the cerebral cortex. Compared to age-matched wild type control, P301S transgenic mice exhibit significant transcriptomic alterations. We have observed age-dependent neuroinflammatory gene expression changes in both wild type and P301S transgenic mice where tau overexpression further promoted the expression of neuroinflammatory genes in 10-month old P301S transgenic mice. Moreover, functional gene network analyses (gene ontology and pathway enrichment) and prospective target protein interactions predicted the potential involvement of multiple immune and inflammatory pathways that may contribute to tau-mediated neuronal pathology. Our current study on P301S transgenic mice model revealed for the first time, the differences of gene expression patterns in both early and late stage of tau pathology in cerebral cortex. Our analyses also revealed that tau overexpression alone induces multiple inflammatory and immune transcriptomic changes and may provide a roadmap to elucidate the targets of anti-inflammatory therapeutic strategy focused on tau pathology and related neurodegenerative diseases.
Subject(s)
Cerebral Cortex/metabolism , Encephalitis/metabolism , Transcriptome , tau Proteins/metabolism , Age Factors , Animals , Cerebral Cortex/pathology , Disease Progression , Encephalitis/genetics , Gene Expression Profiling , Humans , Male , Mice, Transgenic , Mutation , Phosphorylation , Protein Interaction Maps , tau Proteins/geneticsABSTRACT
Mutations in the parkin gene cause autosomal recessive familial Parkinson's disease (PD). Parkin-deficient mouse models fail to recapitulate nigrostriatal dopaminergic neurodegeneration as seen in PD, but produce deficits in dopaminergic neurotransmission and noradrenergic-dependent behavior. Since sporadic PD is thought to be caused by a combination of genetic susceptibilities and environmental factors, we hypothesized that neurotoxic insults from catecholaminergic toxins would render parkin knockout mice more vulnerable to neurodegeneration. Accordingly, we investigated the susceptibility of catecholaminergic neurons in parkin knockout mice to the potent dopaminergic and noradrenergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) respectively. We report that nigrostriatal dopaminergic neurons in parkin knockout mice do not show increased susceptibility to the parkinsonian neurotoxin, MPTP, in acute, subacute and chronic dose regimens of the neurotoxin. Additionally, parkin knockout mice do not show increased vulnerability to the noradrenergic neurotoxin, DSP-4, regarding levels of norepinephrine in cortex, brain stem and spinal cord. These findings suggest that absence of parkin in mice does not increase susceptibility to the loss of catecholaminergic neurons upon exposure to both dopaminergic and noradrenergic neurotoxins.
Subject(s)
Catecholamines/metabolism , Locus Coeruleus/metabolism , Neurons/metabolism , Parkinsonian Disorders/metabolism , Substantia Nigra/metabolism , Ubiquitin-Protein Ligases/genetics , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Benzylamines/toxicity , Cell Survival/genetics , Cytoprotection/genetics , Female , Genetic Predisposition to Disease/genetics , Immunity, Innate/genetics , Locus Coeruleus/drug effects , Locus Coeruleus/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/drug effects , Neurotoxins/toxicity , Norepinephrine/metabolism , Parkinsonian Disorders/genetics , Parkinsonian Disorders/physiopathology , Substantia Nigra/drug effects , Substantia Nigra/physiopathologyABSTRACT
Mutations in the human parkin gene (huParkin) are the predominant genetic cause of familial parkinsonism. The huParkin locus, spanning about 1.4 Mb, is one of the largest in the human genome. Despite its huge size, huParkin codes for a rather short transcript of about 4.5 kb. To gain an insight into the structure, function and evolutionary history of huParkin, we have characterized the pufferfish [Fugu rubripes (Fugu)] ortholog of huParkin. A remarkable feature of the Fugu parkin gene (fuparkin) is its unusually compact size. It spans only about 4 kb and is thus 350-fold smaller than its human ortholog. The Fugu and human parkin genes are otherwise highly similar in their genomic organization and expression pattern. Furthermore, like human Parkin, Fugu parkin also functions as an ubiquitin ligase. These shared features between fuparkin and huParkin suggest that the physiological function and regulation of the parkin gene are conserved during the evolution of vertebrates. Conceivably, the compact locus of fuparkin could serve as a useful model to understand the transcriptional regulation of huParkin.
