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Biomedical subjects

Ted M Dawson

Publications and source records attributed to Ted M Dawson.

At least 55 records · Page 3Linked to original sources
PubMed2005

The involvement of nitric oxide in the enhanced expression of mu-opioid receptors during intestinal inflammation in mice.

Intestinal inflammation enhances the potency of mu-opioid receptor (MOR) agonists inhibiting gastrointestinal transit and increases the expression of MOR in mice intestine. The precise mechanisms implicated in the increased expression of MOR during intestinal inflammation are not known. The aim of the study is to evaluate if nitric oxide released during intestinal inflammation could modulate MOR gene expression and affect gastrointestinal transit. Intestinal inflammation was induced by the intragastric administration of croton oil. In CD-1 mice, with and without inflammation, we evaluated the anti-transit effects of morphine in animals treated with NOS inhibitors (L-NAME and L-NIL) and the intestinal levels of iNOS enzyme mRNA. The anti-transit effects of morphine and the expression of MOR mRNA in the gut of wild-type (WT) and iNOS-/- mice were also assessed. Gastrointestinal transit was measured with charcoal meal and mRNA levels determined by real-time PCR. In CD-1 mice, inflammation induced a 10-fold increase (P<0.0001) in iNOS mRNA levels in the gut. The absence of iNOS gene and treatment of CD-1 mice with L-NAME or L-NIL abolished the increased antitransit effects of morphine observed during inflammation. Moreover, although the basal levels of MOR mRNA were similar in WT and iNOS animals (-/-), intestinal inflammation only increased the MOR expression in the gut of WT (P<0.01) but not in iNOS-/- mice. The results suggest that nitric oxide derived from the increased expression of iNOS is implicated in the enhanced effects of morphine and in the upregulation of MOR gene transcription observed during intestinal inflammation.

Animals↗
PubMed2005

Alterations in the solubility and intracellular localization of parkin by several familial Parkinson's disease-linked point mutations.

Mutations in the parkin gene, which encodes a ubiquitin ligase, are currently recognized as the main contributor to familial forms of Parkinson's disease (PD). A simple assumption about the effects of PD-linked mutations in parkin is that they impair or ablate the enzyme activity. However, a number of recent studies, including ours, have indicated that many disease-linked point mutants of parkin retain substantial catalytic activity. To understand how the plethora of mutations on parkin contribute to its dysfunction, we have conducted a systematic analysis of a significant number of parkin point mutants (22 in total), which represent the majority of parkin missense/nonsense mutations reported to date. We found that more than half of these mutations, including many located outside of the parkin RING fingers, produce alteration in the solubility of parkin which influences its detergent extraction property. This mutation-mediated alteration in parkin solubility is also associated with its propensity to form intracellular, aggresome-like, protein aggregates. However, they do not represent sites where parkin substrates become sequestered. As protein aggregation sequesters the functional forms away from their normal sites of action, our results suggest that alterations in parkin solubility and intracellular localization may underlie the molecular basis of the loss of function caused by several of its mutations.

Cell Line↗
PubMed2005

Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons.

Septin 5, a parkin substrate, is a vesicle- and membrane-associated protein that plays a significant role in inhibiting exocytosis. The regulatory function of Septin 5 in dopaminergic (DAergic) neurons of substantia nigra (SN), maintained at relatively low levels, has not yet been delineated. As loss of function mutations of parkin are the principal cause of a familial Parkinson's disease, a prevailing hypothesis is that the loss of parkin activity results in accumulation of Septin 5 which confers neuron-specific toxicity in SN-DAergic neurons. In vitro and in vivo models were used to support this hypothesis. In our well-characterized DAergic SN4741 cell model, acute accumulation of elevated levels of Septin 5, but not synphilin-1 (another parkin substrate), resulted in cytotoxic cell death that was markedly reduced by parkin co-transfection. A transgenic mouse model expressing a dominant negative parkin mutant accumulated moderate levels of Septin 5 in SN-DAergic neurons. These mice acquired a progressive l-DOPA responsive motor dysfunction that developed despite a 25% higher than normal level of striatal dopamine (DA) and no apparent loss of DAergic neurons. The phenotype of this animal, increased striatal dopamine and reduced motor function, was similar to that observed in parkin knockout animals, suggesting a common DAergic alteration. These data suggest that a threshold level of Septin 5 accumulation is required for DAergic cell loss and that l-DOPA-responsive motor deficits can occur even in the presence of elevated DA.

Animals↗
PubMed2005

Molecular pathophysiology of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that results primarily from the death of dopaminergic neurons in the substantia nigra. Although the etiology of PD is incompletely understood, the recent discovery of genes associated with rare monogenic forms of the disease, together with earlier studies and new experimental animal models, has provided important and novel insight into the molecular pathways involved in disease pathogenesis. Increasing evidence indicates that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction may represent the principal molecular pathways or events that commonly underlie the pathogenesis of sporadic and familial forms of PD .

Animals↗
PubMed2004

Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases.

In order to understand better the neuropathological substrate of dementia in Parkinson's disease (PD) and to examine its interactions with Alzheimer's disease (AD), we examined autopsy brains from 21 cases of PD and Lewy body disease (LBD) with dementia. We separated brains in two groups according to the presence of Abeta deposits. In brains without Abeta, we found few or no Lewy bodies (LB) in the cerebral cortex. By contrast, in brains with Abeta, we observed significant increases in LB in the cerebral cortex (p < 0.01) and alpha-synuclein immunoreactive lesions in the cingulate cortex (p < 0.01). Immunoblots of alpha-synuclein from cingulate cortex in brains with Abeta showed significantly higher levels of insoluble alpha-synuclein compared to brains without Abeta. Our observations indicate that in cases of PD with dementia, the neocortex is not necessarily involved by LB. Furthermore, the presence of Abeta deposits in the cerebral cortex was associated with extensive alpha-synuclein lesions and higher levels of insoluble alpha-synuclein. This suggests that Abeta enhances the development of cortical alpha-synuclein lesions in cases of PD.

Aged↗
PubMed2004

Parkin and Hsp70 sacked by BAG5.

Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, are the major cause of early-onset Parkinson's disease (PD). In this issue of Neuron, Kalia et al. show that the bcl-2-associated athanogene 5 (BAG5) enhances dopamine neuron death in an in vivo model of PD through inhibiting the E3 ligase activity of parkin and the chaperone activity of Hsp70.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The 350-fold compacted Fugu parkin gene is structurally and functionally similar to human Parkin.

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.

Amino Acid Sequence↗
PubMed2004

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality.

The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADP-ribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADP-ribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N'-nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.

Animals↗
PubMed2004

Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death.

The profound neuroprotection observed in poly(ADP-ribose) polymerase-1 (PARP-1) null mice to ischemic and excitotoxic injury positions PARP-1 as a major mediator of neuronal cell death. We report here that apoptosis-inducing factor (AIF) mediates PARP-1-dependent glutamate excitotoxicity in a caspase-independent manner after translocation from the mitochondria to the nucleus. In primary murine cortical cultures, neurotoxic NMDA exposure triggers AIF translocation, mitochondrial membrane depolarization, and phosphatidyl serine exposure on the cell surface, which precedes cytochrome c release and caspase activation. NMDA neurotoxicity is not affected by broad-spectrum caspase inhibitors, but it is prevented by Bcl-2 overexpression and a neutralizing antibody to AIF. These results link PARP-1 activation with AIF translocation in NMDA-triggered excitotoxic neuronal death and provide a paradigm in which AIF can substitute for caspase executioners.

Active Transport, Cell Nucleus↗
PubMed2004

Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress.

The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in alpha-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.

Cell Line, Tumor↗
PubMed2004

Parkin-associated Parkinson's disease.

Mutations in the PARK2 gene coding for parkin cause autosomal recessive juvenile parkinsonism (AR-JP), a familial form of Parkinson's disease (PD). Parkin functions as an E3 ubiquitin ligase, and loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of AR-JP. Recently, the spectrum of genetic, clinical, and pathological findings on AR-JP has been significantly expanded. Moreover, a considerable number of parkin interactors and/or substrates have been identified and characterized, and animal models of parkin deficiency have been generated. In this review, we provide an overview of the most relevant findings and discuss their implications for the pathogenesis of AR-JP and sporadic PD.

Animals↗
PubMed2004

Loss of locus coeruleus neurons and reduced startle in parkin null mice.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized pathologically by degeneration of catecholaminergic neurons of the substantia nigra pars compacta and locus coeruleus, among other regions. Autosomal-recessive juvenile Parkinsonism (ARJP) is caused by mutations in the PARK2 gene coding for parkin and constitutes the most common familial form of PD. The majority of ARJP-associated parkin mutations are thought to be loss of function-mutations; however, the pathogenesis of ARJP remains poorly understood. Here, we report the generation of parkin null mice by targeted deletion of parkin exon 7. These mice show a loss of catecholaminergic neurons in the locus coeruleus and an accompanying loss of norepinephrine in discrete regions of the central nervous system. Moreover, there is a dramatic reduction of the norepinephrine-dependent startle response. The nigrostriatal dopaminergic system does not show any impairment. This mouse model will help gain a better understanding of parkin function and the mechanisms underlying parkin-associated PD.

Adrenergic alpha-Agonists↗
PubMed2004

S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function.

Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.

Alzheimer Disease↗
PubMed2004

CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation.

Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.

Animals↗
PubMed2004

Identification and analysis of plasticity-induced late-response genes.

The excitatory neurotransmitter, glutamate, activates N-methyl-d-aspartate (NMDA) receptors to induce long-lasting synaptic changes through alterations in gene expression. It is believed that these long-lasting changes contribute to learning and memory, drug tolerance, and ischemic preconditioning. To identify NMDA-induced late-response genes, we used a powerful gene-identification method, differential analysis of primary cDNA library expression (DAzLE), and cDNA microarray from primary cortical neurons. We report here that a variety of genes, which we have named plasticity-induced genes (PLINGs), are up-regulated with differential expression patterns after NMDA receptor activation, indicating that there is a broad and dynamic range of long-lasting neuronal responses that occur through NMDA receptor activation. Our results provide a molecular dissection of the activity-dependent long-lasting neuronal responses induced by NMDA receptor activation.

Animals↗
PubMed2004

Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling.

Different cell-death mechanisms control many physiological and pathological processes in humans. Mitochondria play important roles in cell death through the release of pro-apoptotic factors such as cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and caspase-independent cell death, respectively. Poly(ADP-ribose) polymerase 1 (PARP-1) is emerging as an important activator of caspase-independent cell death. PARP-1 generates the majority of long, branched poly(ADP-ribose) (PAR) polymers following DNA damage. Overactivation of PARP-1 initiates a nuclear signal that propagates to mitochondria and triggers the release of AIF. AIF then shuttles from mitochondria to the nucleus and induces peripheral chromatin condensation, large-scale fragmentation of DNA and, ultimately, cytotoxicity. Identification of the pro-death and pro-survival signals in the PARP-1-mediated cell-death program might provide novel therapeutic targets in human diseases.

Apoptosis Inducing Factor↗
PubMed2004

Deadly conversations: nuclear-mitochondrial cross-talk.

Neuronal damage following stroke or neurodegenerative diseases is thought to stem in part from overexcitation of N -methyl-D-aspartate (NMDA) receptors by glutamate. NMDA receptors triggered neurotoxicity is mediated in large part by activation of neuronal nitric oxide synthase (nNOS) and production of nitric oxide (NO). Simultaneous production of superoxide anion in mitochondria provides a permissive environment for the formation of peroxynitrite (ONOO-). Peroxynitrite damages DNA leading to strand breaks and activation of poly(ADP-ribose) polymerase-1 (PARP-1). This signal cascade plays a key role in NMDA excitotoxicity, and experimental models of stroke and Parkinson's disease. The mechanisms of PARP-1-mediated neuronal death are just being revealed. While decrements in ATP and NAD are readily observed following PARP activation, it is not yet clear whether loss of ATP and NAD contribute to the neuronal death cascade or are simply a biochemical marker for PARP-1 activation. Apoptosis-inducing factor (AIF) is normally localized to mitochondria but following PARP-1 activation, AIF translocates to the nucleus triggering chromatin condensation, DNA fragmentation and nuclear shrinkage. Additionally, phosphatidylserine is exposed and at a later time point cytochrome c is released and caspase-3 is activated. In the setting of excitotoxic neuronal death, AIF toxicity is caspase independent. These observations are consistent with reports of biochemical features of apoptosis in neuronal injury models but modest to no protection by caspase inhibitors. It is likely that AIF is the effector of the morphologic and biochemical events and is the commitment point to neuronal cell death, events that occur prior to caspase activation, thus accounting for the limited effects of caspase inhibitors. There exists significant cross talk between the nucleus and mitochondria, ultimately resulting in neuronal cell death. In exploiting this pathway for the development of new therapeutics, it will be important to block AIF translocation from the mitochondria to the nucleus without impairing important physiological functions of AIF in the mitochondria.

Animals↗