Loss of parkin function is responsible for the majority of autosomal recessive parkinsonism. Here, we show that parkin is not only a stress-protective, but also a stress-inducible protein. Both ...mitochondrial and endoplasmic reticulum (ER) stress induce an increase in parkin-specific mRNA and protein levels. The stress-induced upregulation of parkin is mediated by ATF4, a transcription factor of the unfolded protein response (UPR) that binds to a specific CREB/ATF site within the parkin promoter. Interestingly, c-Jun can bind to the same site, but acts as a transcriptional repressor of parkin gene expression. We also present evidence that mitochondrial damage can induce ER stress, leading to the activation of the UPR, and thereby to an upregulation of parkin expression. Vice versa, ER stress results in mitochondrial damage, which can be prevented by parkin. Notably, the activity of parkin to protect cells from stress-induced cell death is independent of the proteasome, indicating that proteasomal degradation of parkin substrates cannot explain the cytoprotective activity of parkin. Our study supports the notion that parkin has a role in the interorganellar crosstalk between the ER and mitochondria to promote cell survival under stress, suggesting that both ER and mitochondrial stress can contribute to the pathogenesis of Parkinson's disease.
Dopaminergic neurons in the mammalian brain have received substantial attention in the past given their fundamental role in several body functions and behaviours. The largest dopaminergic population ...is found in two nuclei of the ventral midbrain. Cells of the substantia nigra pars compacta are involved in the control of voluntary movements and postural reflexes, and their degeneration in the adult brain leads to Parkinson's disease. Cells of the ventral tegmental area modulate rewarding and cognitive behaviours, and their dysfunction is involved in the pathogenesis of addictive disorders and schizophrenia. Because of their clinical relevance, the embryonic development and maintenance of the midbrain dopaminergic cell groups in the adult have been intensively studied in recent years. In the present review, we provide an overview of the mechanisms and factors involved in the development of dopaminergic neurons in the mammalian brain, with a special emphasis on the midbrain dopaminergic population.
The International Knockout Mouse Consortium (IKMC;
http://www.mousephenotype.org
) has generated mutations in almost every protein-coding mouse gene and is completing the companion Cre driver ...resource to expand tissue-specific conditional mutagenesis. Accordingly, the IKMC has carried out high-throughput gene trapping and targeting producing conditional mutations in murine embryonic stem cells in more than 18,500 genes, from which at least 4900 mutant mouse lines have been established to date. This resource is currently being upgraded with more powerful tools, such as visualization and manipulation cassettes that can be easily introduced into IKMC alleles for multifaceted functional studies. In addition, we discuss how existing IKMC products can be used in combination with CRISPR technology to accelerate genome engineering projects. All information and materials from this extraordinary biological resource together with coordinated phenotyping efforts can be retrieved at
www.mousephenotype.org
. The comprehensive IKMC knockout resource in combination with an extensive set of modular gene cassettes will continue to enhance functional gene annotation in the future and solidify its impact on biomedical research.
The pharmacokinetic and pharmacodynamic effects of inhaled corticosteroids (ICS) have shaped the efficacy and safety of these agents in the treatment of asthma. Important pharmacokinetic and ...pharmacodynamic characteristics that can enhance the efficacy of ICS include small particle size, high glucocorticoid-receptor-binding affinity, long pulmonary residence time and lipid conjugation. These characteristics can increase or prolong the anti-inflammatory effects of an ICS. Important pharmacokinetic characteristics that can enhance the safety of ICS include on-site activation in the lung, low oropharyngeal exposure, negligible oral bioavailability, high protein-binding and rapid systemic clearance. The degree of oropharyngeal exposure is relevant to local side-effects, such as oropharyngeal candidiasis, dysphonia and coughing. Pharmacokinetic properties that influence the degree of systemic exposure are relevant to the pharmacodynamic effect of ICS-induced hypothalamic-pituitary-adrenal axis suppression and cortisol suppression, an indicator of potential long-term systemic side-effects, such as reduced growth velocity and bone density, fractures, and skin bruising and thinning. Therefore, significant differences in the pharmacokinetic and pharmacodynamic characteristics of the currently available inhaled corticosteroids warrant careful consideration when used in clinical practice as they may result in differences in efficacy and local and systemic safety profiles.
Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Ca
1.2, rank among the most consistent and replicable genetics findings in psychiatry ...and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Ca
1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Ca
1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Ca
1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.
PINK1 (phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced kinase 1), a Parkinson's disease-associated gene, was identified originally because of its induction by the ...tumor-suppressor PTEN. PINK1 promotes cell survival and potentially metastatic functions and protects against cell stressors including chemotherapeutic agents. However, the mechanisms underlying PINK1 function in cancer cell biology are unclear. Here, using several model systems, we show that PINK1 deletion significantly reduced cancer-associated phenotypes including cell proliferation, colony formation and invasiveness, which were restored by human PINK1 overexpression. Results show that PINK1 deletion causes major defects in cell cycle progression in immortalized mouse embryonic fibroblasts (MEFs) from PINK1(-/-) mice, and in BE(2)-M17 cells stably transduced with short hairpin RNA against PINK1. Detailed cell cycle analyses of MEF cell lines from several PINK1(-/-) mice demonstrate an increased proportion of cells in G2/M and decreased number of cells in G1 following release from nocodazole block. This was concomitant with increased double and multi-nucleated cells, a reduced ability to undergo cytokinesis and to re-enter G1, and significant alterations in cell cycle markers, including failure to increase cyclin D1, all indicative of mitotic arrest. PINK1(-/-) cells also demonstrated ineffective cell cycle exit following serum deprivation. Cell cycle defects associated with PINK1 deficiency occur at points critical for cell division, growth and stress resistance in cancer cells were rescued by ectopic expression of human PINK1 and demonstrated PINK1 kinase dependence. The importance of PINK1 for cell cycle control is further supported by results showing that cell cycle deficits induced by PINK1 deletion were linked mechanistically to aberrant mitochondrial fission and its regulation by dynamin-related protein-1 (Drp1), known to be critical for progression of mitosis. Our data indicate that PINK1 has tumor-promoting properties and demonstrates a new function for PINK1 as a regulator of the cell cycle.
Abstract The aim of the present study was to further explore the in vivo function of the Leucine-rich repeat kinase 2 ( LRRK2 )-gene, which is mutated in certain familial forms of Parkinson's disease ...(PD). We generated a mouse model harboring the disease-associated point mutation R1441C in the GTPase domain of the endogenous murine LRRK2 gene (LRRK2 R1441C line) and performed a comprehensive analysis of these animals throughout lifespan in comparison with an existing knockdown line of LRRK2 (LRRK2 knockdown line). Animals of both lines do not exhibit severe motor dysfunction or pathological signs of neurodegeneration neither at young nor old age. However, at old age the homozygous LRRK2 R1441C animals exhibit clear phenotypes related to the prodromal phase of PD such as impairments in fine motor tasks, gait, and olfaction. These phenotypes are only marginally observable in the LRRK2 knockdown animals, possibly due to activation of compensatory mechanisms as suggested by in vitro studies of synaptic transmission. Thus, at the organismal level the LRRK2 R1441C mutation does not emerge as a loss of function of the protein, but induces mutation specific deficits. Furthermore, judged by the phenotypes presented, the LRRK2-R1441C knock-in line is a valid preclinical model for the prodromal phase of PD.
The development of novel treatments for rheumatoid arthritis (RA) requires the interplay between clinical observations and studies in animal models. Given the complex molecular pathogenesis and ...highly heterogeneous clinical picture of RA, there is an urgent need to dissect its multifactorial nature and to propose new strategies for preventive, early and curative treatments. Research on animal models has generated new knowledge on RA pathophysiology and aetiology and has provided highly successful paradigms for innovative drug development. Recent focus has shifted towards the discovery of novel biomarkers, with emphasis on presymptomatic and emerging stages of human RA, and towards addressing the pathophysiological mechanisms and subsequent efficacy of interventions that underlie different disease variants. Shifts in the current paradigms underlying RA pathogenesis have also led to increased demand for new (including humanised) animal models. There is therefore an urgent need to integrate the knowledge on human and animal models with the ultimate goal of creating a comprehensive 'pathogenesis map' that will guide alignment of existing and new animal models to the subset of disease they mimic. This requires full and standardised characterisation of all models at the genotypic, phenotypic and biomarker level, exploiting recent technological developments in 'omics' profiling and computational biology as well as state of the art bioimaging. Efficient integration and dissemination of information and resources as well as outreach to the public will be necessary to manage the plethora of data accumulated and to increase community awareness and support for innovative animal model research in rheumatology.
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