Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1؊͞؊ mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1؊͞؊ embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1؊͞؊ mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults. P arkinson's disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, akinesia, and postural instability (1). The cause of PD remains unknown, but epidemiological and genetic studies have suggested that the observed loss of dopaminergic neurons in PD is due to defects in common intracellular signaling pathways (2). Genes linked to familial PD include ␣-synuclein (3), Parkin (4), UCH-L1 (5), PINK1 (6), and dardarin (7). Proteins encoded by these genes are thought to be involved in protein aggregation and proteasome function, processes which, when disrupted in model systems, can also result in noninherited forms of PD (8). Recently, loss-of-function mutations in the DJ-1 locus were found in families with autosomal recessive early-onset PD (9). Additional studies have confirmed other DJ-1 mutations in various PD cohorts (10). DJ-1 was initially cloned as a putative oncogene (11) and as part of an RNA-binding complex (12). DJ-1 is highly expressed by normal astrocytes (13) and has been implicated in fertilization (14) and tumorigenesis (15,16). Studies of the crystal structure of DJ-1 (17) suggest that a particular DJ-1 mutation (L166P) reduces DJ-1 protein stability (18)(19)(20), resulting in degradation through the ubiquitin-proteasome system (21, 22). However, the physiological function of DJ-1 remains largely unknown.Motor impairments in PD patients result from inhibition of the nigrostriatal motor pathway. This inhibition is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) (8). The cause of the dopaminergic neuron loss remains unknown, but oxidative stress leading to apoptotic neuronal death has been implicated (23). Various neurotoxic paradigms have been studied in an effort to reproduce oxidative stress leading to neuronal loss in the SNc. Of these, administration of the well characterized meperidine analogue 1-methyl-4-phenyl-1,2,3,6-te...
Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas1 and cytogenetically normal acute myeloid leukaemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.
Diverse functions have been reported for lipocalin 2. To investigate these functions in vivo, we generated gene-targeted lipocalin 2-deficient mice (Lcn2 ؊/؊ mice). In vitro studies have suggested that lipocalin 2 is important for cellular apoptosis induced by IL-3 withdrawal, and for the induction of kidney differentiation during embryogenesis. Analysis of Lcn2 ؊/؊ mice showed normal cell death upon IL-3 withdrawal and normal kidney development. However, we found that Lcn2 ؊/؊ mice exhibited an increased susceptibility to bacterial infections, in keeping with the proposed function of lipocalin 2 in iron sequestration. Neutrophils isolated from Lcn2 ؊/؊ mice showed significantly less bacteriostatic activity compared with WT controls. The bacteriostatic property of the WT neutrophils was abolished by the addition of exogenous iron, indicating that the main function of lipocalin 2 in the antibacterial innate immune response is to limit this essential element. Another important function ascribed to lipocalin 2 has been its protective role against kidney ischemia-reperfusion injury. We analyzed Lcn2 ؊/؊ mice using a mouse model for severe renal failure and could not detect any significant differences compared with their WT littermates.24p3 ͉ bacteriostatic ͉ kidney ischemia-reperfusion injury ͉ NGAL
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