Showing papers by "Valina L. Dawson published in 2011"
TL;DR: The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation, whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitIn ligase, parkin.
825 citations
TL;DR: Advances obtained from models of dominant mutations in α-synuclein and LRRK2 as well as recessive PINK1, parkin and DJ-1 mutations are reviewed, highlighting the likelihood of common mechanisms fundamental to the etiology of both familial and sporadic Parkinson's disease.
Abstract: Genetic studies have provided valuable insight into the pathological mechanisms underlying Parkinson's disease (PD). The elucidation of genetic components to what was once largely considered a nongenetic disease has given rise to a multitude of cell and animal models enabling the dissection of molecular pathways involved in disease etiology. Here, we review advances obtained from models of dominant mutations in α-synuclein and LRRK2 as well as recessive PINK1, parkin and DJ-1 mutations. Recent genome-wide association studies have implicated genetic variability at two of these loci, α-synuclein and LRRK2, as significant risk factors for developing sporadic PD. This, coupled with the established role of mitochondrial impairment in both familial and sporadic PD, highlights the likelihood of common mechanisms fundamental to the etiology of both.
378 citations
TL;DR: This study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner, and will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD.
Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD.
368 citations
TL;DR: A mechanism for PARP-1 to initiate AIF-mediated cell death is suggested and indicate that AIF’s bioenergetic cell survival–promoting functions are separate from its effects as a mitochondrially derived death effector.
Abstract: Overactivation of the DNA repair enzyme PARP-1 [poly(ADP-ribose) (PAR) polymerase-1] leads to “parthanatos,” a form of cell death that is distinct from apoptosis and necrosis and that depends on release of apoptosis-inducing factor (AIF) from mitochondria. Here, Wang et al . showed that PAR bound directly to AIF, disrupting AIF’s association with the mitochondria and allowing it to translocate to the nucleus to mediate cell death. Moreover, mutation of the PAR binding site of AIF enabled the authors to separate AIF’s role in parthanatos from its function in mitochondrial respiration. Identification of AIF as a PAR-binding protein could potentially lead to the development of compounds that inhibit this interaction, protecting against parthanatos, or compounds that mimic it and thereby promote parthanatos as an agent of death in malignant cells.
360 citations
TL;DR: Iduna is defined as a PAR-dependent E3 ligase that regulates cell survival and DNA repair and targets PARP1 for proteasomal degradation.
Abstract: Ubiquitin mediated protein degradation is crucial for regulation of cell signaling and protein quality control. Poly(ADP-ribose) (PAR) is a cell-signaling molecule that mediates changes in protein function through binding at PAR binding sites. Here we characterize the PAR binding protein, Iduna, and show that it is a PAR-dependent ubiquitin E3 ligase. Iduna’s E3 ligase activity requires PAR binding because point mutations at Y156A and R157A eliminate Iduna’s PAR binding and Iduna’s E3 ligase activity. Iduna’s E3 ligase activity also requires an intact really interesting new gene (RING) domain because Iduna possessing point mutations at either H54A or C60A is devoid of ubiquitination activity. Tandem affinity purification reveals that Iduna binds to a number of proteins that are either PARsylated or bind PAR including PAR polymerase-1, 2 (PARP1, 2), nucleolin, DNA ligase III, KU70, KU86, XRCC1, and histones. PAR binding to Iduna activates its E3 ligase function, and PAR binding is required for Iduna ubiquitination of PARP1, XRCC1, DNA ligase III, and KU70. Iduna’s PAR-dependent ubiquitination of PARP1 targets it for proteasomal degradation. Via PAR binding and ubiquitin E3 ligase activity, Iduna protects against cell death induced by the DNA damaging agent N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and rescues cells from G1 arrest and promotes cell survival after γ-irradiation. Moreover, Iduna facilitates DNA repair by reducing apurinic/apyrimidinic (AP) sites after MNNG exposure and facilitates DNA repair following γ-irradiation as assessed by the comet assay. These results define Iduna as a PAR-dependent E3 ligase that regulates cell survival and DNA repair.
206 citations
TL;DR: Ida is a PAR polymer–binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions, defining Iduna as the first known endogenous inhibitor of parthanatos.
Abstract: Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-induced survival protein that is neuroprotective against glutamate NMDA receptor-mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer-induced cell death (parthanatos). Iduna's protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders.
188 citations
141 citations
TL;DR: It is demonstrated that CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency, and this work employs a chemoproteomics strategy to identify potent, selective, and metabolically stable L RRK2 inhibitors.
Abstract: Leucine-rich repeat kinase-2 (LRRK2) mutations are the most important cause of familial Parkinson's disease and non-selective inhibitors are protective in rodent disease models. Due to their poor potency and selectivity, the neuroprotective mechanism of these tool compounds has remained elusive so far and it is still unknown whether selective LRRK2 inhibition can attenuate mutant LRRK2-dependent toxicity in human neurons. Here, we employ a chemoproteomics strategy to identify potent, selective and metabolically stable LRRK2 inhibitors. We demonstrate that CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency. These precise chemical probes further validate this emerging therapeutic strategy. They will enable more detailed studies of LRRK2-dependent signaling and pathogenesis and accelerate drug discovery.
128 citations
TL;DR: Findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of L RRK2 activity can have a disease-modifying effect and suggests that inhibitionof LRRk2 holds promise as a treatment for PD.
Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) have been identified as a genetic cause of familial Parkinson's disease (PD) and have also been found in the more common sporadic form of PD, thus positioning LRRK2 as important in the pathogenesis of PD. Biochemical studies of the disease-causing mutants of LRRK2 implicates an enhancement of kinase activity as the basis of neuronal toxicity and thus possibly the pathogenesis of PD due to LRRK2 mutations. Previously, a chemical library screen identified inhibitors of LRRK2 kinase activity. Here, two of these inhibitors, GW5074 and sorafenib, are shown to protect against G2019S LRRK2-induced neurodegeneration in vivo in Caenorhabditis elegans and in Drosophila. These findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of LRRK2 activity can have a disease-modifying effect. This suggests that inhibition of LRRK2 holds promise as a treatment for PD.
123 citations
TL;DR: Recent work linking the microRNA pathway to Parkinson's disease is reviewed to highlight the importance of microRNAs in the nervous system development, function and disease.
108 citations
TL;DR: An AAA+ ATPase Thorase is described and characterized, which regulates the expression of surface AMPAR and thereby regulates synaptic plasticity and learning and memory in Thorase null mice.
TL;DR: A role for iron is suggested in PD pathogenesis and pharmacological inhibition of autophagy reverses cell death mediated by Fe2+ overloading and provides a mechanism underlying Fe2-mediated cell death.
TL;DR: The in vivo interaction of mouse and human α-synuclein with the potent parkinsonian neurotoxin, MPTP is investigated to provide new mechanistic insights on the role α- synuclein in modulating neurodegenerative phenotypes by regulation of Akt-mediated cell survival signaling in vivo.
Abstract: Genetic and biochemical abnormalities of α-synuclein are associated with the pathogenesis of Parkinson's disease. In the present study we investigated the in vivo interaction of mouse and human α-synuclein with the potent parkinsonian neurotoxin, MPTP. We find that while lack of mouse α-synuclein in mice is associated with reduced vulnerability to MPTP, increased levels of human α-synuclein expression is not associated with obvious changes in the vulnerability of dopaminergic neurons to MPTP. However, expressing human α-synuclein variants (human wild type or A53T) in the α-synuclein null mice completely restores the vulnerability of nigral dopaminergic neurons to MPTP. These results indicate that human α-synuclein can functionally replace mouse α-synuclein in regard to vulnerability of dopaminergic neurons to MPTP-toxicity. Significantly, α-synuclein null mice and wild type mice were equally sensitive to neurodegeneration induced by 2′NH2-MPTP, a MPTP analog that is selective for serotoninergic and noradrenergic neurons. These results suggest that effects of α-synuclein on MPTP like compounds are selective for nigral dopaminergic neurons. Immunoblot analysis of β-synuclein and Akt levels in the mice reveals selective increases in β-synuclein and phosphorylated Akt levels in ventral midbrain, but not in other brain regions, of α-synuclein null mice, implicating the α-synuclein-level dependent regulation of β-synuclein expression in modulation of MPTP-toxicity by α-synuclein. Together these findings provide new mechanistic insights on the role α-synuclein in modulating neurodegenerative phenotypes by regulation of Akt-mediated cell survival signaling in vivo.
TL;DR: expression profiling following induction of neuronal activity by electroconvulsive shock demonstrates that most miRNA show a biphasic pattern of expression: rapid induction of specific mature miRNA expression followed by a decline in expression, which has important implications into how miRNAs influence activity-dependent translational control.
Abstract: Neuronal activity regulates a broad range of processes in the hippocampus, including the precise regulation of translation. Disruptions in proper translational control in the nervous system are associated with a variety of disorders that fall in the autistic spectrum. MicroRNA (miRNA) represent a relatively recently discovered player in the regulation of translation in the nervous system. We have conducted an in depth analysis of how neuronal activity regulates miRNA expression in the hippocampus. Using deep sequencing we exhaustively identify all miRNAs, including 15 novel miRNAs, expressed in hippocampus of the adult mouse. We identified 119 miRNAs documented in miRBase but less than half of these miRNA were expressed at a level greater than 0.1% of total miRNA. Expression profiling following induction of neuronal activity by electroconvulsive shock demonstrates that most miRNA show a biphasic pattern of expression: rapid induction of specific mature miRNA expression followed by a decline in expression. These results have important implications into how miRNAs influence activity-dependent translational control.
TL;DR: A reciprocal connection between loss of GBA activity and the accumulation of α-synuclein in lysosomes that establishes a bidirectional positive feedback loop with pathogenic consequences is reported.
Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. Although many of the causes of PD remain unclear, a consistent finding is the abnormal accumulation of the protein α-synuclein. In a recent issue of Cell, Mazzuli et al. provide a molecular explanation for the unexpected link between PD and Gaucher's disease, a glycolipid lysosomal storage disorder caused by loss of the enzyme glucocerebrosidase (GBA). They report a reciprocal connection between loss of GBA activity and the accumulation of α-synuclein in lysosomes that establishes a bidirectional positive feedback loop with pathogenic consequences. Understanding how lysosomes are implicated in PD may reveal new therapeutic targets for treating this disease.
Patent•
11 Nov 2011
TL;DR: Parkin Interacting Substrate, PARIS (ZNF746) is identified in this article, which provides a molecular mechanism for neurodegeneration due to parkin inactivation.
Abstract: Parkinson's disease is caused by the preferential loss of substantia nigra dopamine neurons A Parkin Interacting Substrate, PARIS (ZNF746) is identified The levels of PARIS are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human brain Parkinson's disease patients PARIS represses the expression of the transcriptional co-activator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons that is PARIS dependent Overexpression of PARIS causes selective loss of DA neurons in the substantia nigra, which is reversed by either parkin or PGC-1α co-expression The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation
01 Jan 2011
TL;DR: The AAA + ATPase Thorase is described and characterized, which regulates the expression of surface AMPAR, which mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex.
Abstract: SUMMARY The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA + ATPase Thorase, which regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP, and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. This study identifies an AAA + ATPase that plays a critical role in
Patent•
11 Nov 2011
TL;DR: In this paper, the compositions and induction strategies disclosed herein have use for acute injuries such as stroke or trauma, and would be extremely useful in treating patients undergoing cardiac bypass surgery, neurosurgery or other surgical cohorts where ischemia is a risk.
Abstract: Research into neuroprotective mechanisms has at its heart the goal of developing new therapeutic strategies to treat patients. For example, the compositions and induction strategies disclosed herein have use for acute injuries such as stroke or trauma, and would be extremely useful in treating patients undergoing cardiac bypass surgery, neurosurgery or other surgical cohorts where ischemia is a risk. Further, patients with subarachnoid hemorrhage, transient ischemic attacks, soldiers at risk for blast injury or patients suffering from chronic neurodegenerative diseases would also benefit from enhanced neuronal survival based upon the techniques and compositions disclosed herein. In addition, protecting against cell death by, for example, interfering with PAR polymer signaling via the compositions and processes disclosed herein, offers new therapeutic strategies for the treatment of neurologic disorders.
Patent•
11 Nov 2011
TL;DR: In this article, the PAR-binding motif (PBM) was used to prevent or disrupt PAR-related release from the mitochondria, which is a key step in the programmed cell death process known as parthanatos.
Abstract: [00187] Apoptosis inducing factor ("AIF") contains a PAR-binding motif ("PBM") that binds to Poly(ADP-ribose) ("PAR"). Binding of PAR to AIF via the PBM is required for AIF release from the mitochondria to occur, and that this PAR-related release is a key step in the programmed cell death process known as parthanatos, both in vitro and in vivo. Preventing or disrupting this release can inhibit parthanatos and thus be the basis for treatments for patients suffering from diseases or medical conditions during which parthanatos commonly occurs, including Parkinson's disease or diabetes, or patients who have had and are recovering from heart attack, stroke and other ischemia reperfusion-related injuries. Alternatively, agents could be identified that enhance the release of AIF, thereby promoting parthanatos and serving as potential anti-tumor chemotherapeutic agents.
Patent•
11 Nov 2011
TL;DR: The facteur induisant l'apoptose (« AIF '') contient un motif de liaison a PAR (« PBM ») which se lie au poly(ADP-ribose) (« PAR »), and cette liberation associee a PAR est une etapecle dans le processus de mort cellulaire programmee, connue en tant que parthanatose, a la fois in vitro and in vivo.
Abstract: Selon l'invention, le facteur induisant l'apoptose (« AIF ») contient un motif de liaison a PAR (« PBM ») qui se lie au poly(ADP-ribose) (« PAR »). La liaison de PAR a AIF par l'intermediaire du PBM est necessaire pour la liberation d'AIF de la mitochondrie, et cette liberation associee a PAR est une etape-cle dans le processus de mort cellulaire programmee, connue en tant que parthanatose, a la fois in vitro et in vivo . La prevention ou la perturbation de cette liberation peut inhiber la parthanatose et par consequent etre la base de traitements pour des patients souffrant de maladies ou d'etats medicaux au cours desquels la parthanatose a communement lieu, comprenant la maladie de Parkinson ou le diabete, ou des patients qui ont eu une crise cardiaque, un accident vasculaire cerebral et d'autres lesions associees a une ischemie de reperfusion, et qui sont en convalescence. En variante, des agents ont pu etre identifies qui augmentent la liberation d'AIF, promouvant ainsi la parthanatose et servant en tant qu'agents chimiotherapiques anti-tumoraux potentiels.