Parkinson Disease: Dawson VL

Moore DJ, Dawson VL, Dawson TM. · No affiliation provided · Ann Neurol. · Pubmed #12953259 No free full text.

This publication has no abstract.

Gupta A, Dawson VL, Dawson TM. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Ann Neurol. · Pubmed #19127586 No free full text.

Abstract: Currently, there is no proven neuroprotective or neurorestorative therapy for Parkinson's disease (PD). Several advances in the genetics of PD have created an opportunity to develop mechanistic-based therapies that hold particular promise for identifying agents that slow and even halt the progression of PD, as well as restore function. Here we review many of the advances in the last decade regarding the identification of new targets for the treatment of PD based on understanding the molecular mechanisms of how mutations in genes linked to PD cause neurodegeneration.

Savitt JM, Dawson VL, Dawson TM. · Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. · J Clin Invest. · Pubmed #16823471 links to  free full text

Abstract: Parkinson disease (PD) is a relatively common disorder of the nervous system that afflicts patients later in life with tremor, slowness of movement, gait instability, and rigidity. Treatment of these cardinal features of the disease is a success story of modern science and medicine, as a great deal of disability can be alleviated through the pharmacological correction of brain dopamine deficiency. Unfortunately these therapies only provide temporary, though significant, relief from early symptoms and do not halt disease progression. In addition, pathological changes outside of the motor system leading to cognitive, autonomic, and psychiatric symptoms are not sufficiently treated by current therapies. Much as the discovery of dopamine deficiency led to powerful treatments for motor symptoms, recent discoveries concerning the role of specific genes in PD pathology will lead to the next revolution in disease therapy. Understanding why and how susceptible cells in motor and nonmotor regions of the brain die in PD is the first step toward preventing this cell death and curing or slowing the disease. In this review we discuss recent discoveries in the fields of diagnosis and treatment of PD and focus on how a better understanding of disease mechanisms gained through the study of monogenetic forms of PD has provided novel therapeutic targets.

Moore DJ, Dawson VL, Dawson TM. · Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Sci Aging Knowledge Environ. · Pubmed #16407572 No free full text.

Abstract: Mutations in the DJ-1 gene are associated with rare forms of autosomal recessive early-onset Parkinson's disease (PD). Although the precise physiological function of DJ-1 remains obscure, accumulating evidence suggests that DJ-1 may normally function as a redox-sensitive molecular chaperone that can protect against the deleterious effects of oxidative stress, particularly in mitochondria. Recent studies in the fruit fly, Drosophila melanogaster, have shed further light on the biological role of DJ-1. DJ-1-deficient Drosophila models exhibit distinct phenotypes but collectively highlight a prominent neuroprotective role for DJ-1 against oxidative insult. However, Drosophila lacking DJ-1 do not consistently produce a useful PD-like phenotype (that is, they generally fail to exhibit degeneration of neurons that contain the neurotransmitter dopamine), which may reflect putative compensatory neuroprotective mechanisms. DJ-1-deficient fly models further highlight the utility of Drosophila as an important tool for elucidating protein function and for modeling neurodegenerative disease.

Lim KL, Dawson VL, Dawson TM. · Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore. · Neurobiol Aging. · Pubmed #16213628 No free full text.

Abstract: Most, if not all, neurodegenerative diseases are marked by the presence of ubiquitin-positive protein inclusions. How proteins within these inclusion bodies escape proteasomal degradation despite being enriched with ubiquitin remains a conundrum. Current evidence suggests a relationship between proteasomal impairment and inclusion formation, a persuasive explanation for the inability of the cell to remove ubiquitinated protein aggregates. Alternatively, the formation of ubiquitin-enriched inclusion may be uncoupled from the proteasome. Supporting this, we recently uncovered a novel, proteasomal-independent, catalytic activity for the Parkinson disease (PD)-linked ubiquitin ligase, parkin, that significantly enhances the formation of Lewy body (LB)-like inclusions generated in cultured cells by the co-expression of alpha-synuclein and synphilin-1. This unique activity of parkin mediates a non-classical, lysine (K) 63-linked ubiquitin multichain assembly on synphilin-1 that is distinct from the classical, degradation-associated, K48-linked ubiquitination. Interestingly, two other PD-linked gene products, alpha-synuclein and UCHL1, have recently also been associated with K63-linked ubiquitination. Inclusive of parkin, there are therefore now three PD-related gene products that are known to potentiate K63-linked ubiquitination, thus signalling an important functional relationship between this unique mode of ubiquitin tagging and PD pathogenesis. Mechanistically, the involvement of a "non-degradative" mode of ubiquitination in protein inclusion formation is an attractive explanation for how proteins are seemingly stabilized within inclusions.

Chung KK, Dawson TM, Dawson VL. · Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Cell Mol Biol (Noisy-le-grand). · Pubmed #16191392 No free full text.

Abstract: Nitric oxide is a critically important signaling molecule, controlling a wide range of pathways and biological processes. Highly reactive nitric oxide mediates its function through reaction with different molecules directly or indirectly. One of these modifications is the S-nitrosylation of cysteine residues in proteins. S-nitrosylation is emerging as an important redox signaling mechanism and has been found to regulate a broad range of biologic, physiologic and cellular functions. One of the major findings in this area recently is the linkage of nitrosative stress to various neurodegenerative disorders. Oxidative stress has long been regarded as a prime mediator in the development of neurodegeneration as various indices of oxidative stress are readily observed in postmortem studies. A causative role for nitrosative stress in neurodegeneration is just now being appreciated. The direct connection of S-nitrosylation to the pathogenesis of Parkinson's disease in recent studies further provide insights into how imbalance in nitric oxide metabolism can contribute to the development of selective injury and disease.

Moore DJ, West AB, Dawson VL, Dawson TM. · Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Annu Rev Neurosci. · Pubmed #16022590 No free full text.

Abstract: 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 .

Zhang L, Dawson VL, Dawson TM. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Pharmacol Ther. · Pubmed #16005074 No free full text.

Abstract: As a signal molecule, nitric oxide (NO) plays an important role in a variety of signal transduction pathways that are crucial for maintaining the physiologic functions of vascular, respiratory, immune, muscular, and nervous systems. NO and its derivatives are also involved in the pathogenic processes in various types of diseases including, but not limited to, neurodegenerative disorders. Although the molecular mechanisms of how NO contributes to diseases are not completely understood, studies have shown that NO may cause neuronal injury and death by mediation of excitotoxicity, damage of DNA, and/or modification of proteins. Understanding the pathogenic mechanisms of NO and its role in Parkinson's disease (PD) and other neurodegenerative diseases may help to develop novel neuroprotective therapies for these diseases.

West AB, Dawson VL, Dawson TM. · Institute for Cell Engineering, and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Trends Neurosci. · Pubmed #15913799 No free full text.

Abstract: Epidemiological evidence suggests a reduced incidence of many common types of non-smoking-related cancers in individuals with Parkinson's disease (PD). Genes that underlie familial forms of PD are often abnormally expressed in cancer, owing to their differential regulation or mutation. Functional studies implicate these genes in maintenance of the cell cycle, in some cases through interaction in the ubiquitin-proteasome system. Variation in genes associated with familial-linked PD could therefore modify susceptibility to both cancer and PD, implying some degree of overlap in the underlying biochemical dysfunction. When considering the normal function of these PD-linked genes in the periphery and their potential role in cancer, further emphasis might be placed on protein handling relating to cell-cycle control in the etiology of PD.

Koh DW, Dawson TM, Dawson VL. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway St., Suite 711, Baltimore, MD 21205, USA. · Pharmacol Res. · Pubmed #15911329 No free full text.

Abstract: Poly(ADP-ribosyl)ation plays an important role in modulating the cellular response to stress. The extent of poly(ADP-ribosyl)ation, chiefly via the activation of the poly(ADP-ribose) polymerase-1 (PARP-1), correlates with the severity of genotoxic stress and this determines the cellular response. Under mild and moderate stress, it plays important roles in DNA processing and it participates in the proinflammatory/cellular defense via transcriptional regulation. However, severe stress following acute neuronal injury causes the overactivation of PARP-1, which results in unregulated poly(ADP-ribose) (PAR) synthesis and widespread neuronal cell death. Previously, this PARP-1-dependent cell death mechanism was manifest solely through necrosis, but apoptotic mechanisms are also evident. Poly(ADP-ribosyl)ation directly induces the nuclear translocation of apoptosis-inducing factor, which results in caspase-independent cell death significant in many neurodegenerative conditions. Further, the hydrolysis of PAR by poly(ADP-ribose) glycohydrolase (PARG) has a protective role, since the accumulation of PAR leads to cell death by apoptosis. Thus, PAR signaling, regulated by PARP-1 and PARG, mediates cell death. Accordingly, modulation of PAR synthesis or degradation through the targeting of PARP-1 or PARG holds particular promise in the treatment of conditions such as cancer, stroke, and Parkinson's disease.

von Coelln R, Dawson VL, Dawson TM. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Suite 731, Baltimore, MD 21205, USA. · Cell Tissue Res. · Pubmed #15503153 No free full text.

Abstract: 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.

Dawson TM, Dawson VL. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Science. · Pubmed #14593166 No free full text.

Abstract: Parkinson's disease (PD) is a complex disorder with many different causes, yet they may intersect in common pathways, raising the possibility that neuroprotective agents may have broad applicability in the treatment of PD. Current evidence suggests that mitochondrial complex I inhibition may be the central cause of sporadic PD and that derangements in complex I cause alpha-synuclein aggregation, which contributes to the demise of dopamine neurons. Accumulation and aggregation of alpha-synuclein may further contribute to the death of dopamine neurons through impairments in protein handling and detoxification. Dysfunction of parkin (a ubiquitin E3 ligase) and DJ-1 could contribute to these deficits. Strategies aimed at restoring complex I activity, reducing oxidative stress and alpha-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.

Chung KK, Dawson VL, Dawson TM. · Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Carnegie 2-214, Baltimore, Maryland 21287, USA. · J Neurol. · Pubmed #14579120 No free full text.

Abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Recent advances in genetics and pathophysiology have led to new insights into the pathogenesis of PD. Ten loci have been linked to hereditary PD. Mutations in alpha-synuclein and ubiquitin carboxy hydrolase L1 (UchL1) cause autosomal dominant PD and mutations in parkin and DJ-1 cause autosomal recessive PD. alpha-Synuclein has emerged as an important protein in the pathogenesis of PD, as it appears to be the major structural component of Lewy bodies and its accumulation/aggregation seems to play a prominent role in sporadic PD. Mutations in parkin are the most common cause of hereditary PD, and mutations in parkin are thought to lead to a loss of parkin's ubiquitin E3 ligase activity. Derangements in parkin function as well as mutations in UCH-L1 fit with the notion that derangements in the ubiquitin proteasomal pathway (UPP) may play important roles in the demise of dopamine neurons in PD. DJ-1 is a protein of unknown function that is linked to autosomal recessive PD. Oxidative stress and impairment in mitochondrial complex I activity are important in sporadic PD, and there is emerging interest in the role of herbicides, fungicides and insecticides that inhibit mitochondrial complex I activity and their role in contributing to the development of PD. These important findings serve as the foundation for discovering new pathways that may lead to the development of new therapies for PD.

Moore DJ, Dawson VL, Dawson TM. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Neuromolecular Med. · Pubmed #14528055 No free full text.

Abstract: Many neurodegenerative brain amyloidoses, including Alzheimer's and Parkinson's disease, are characterized by selective neuronal loss together with the appearance of intraneuronal ubiquitin-positive proteinaceous aggregates or inclusion bodies. These features usually result from the abnormal accumulation and processing of mutant, misfolded, or damaged intracellular proteins. It has recently become clear that both genetic factors and aberrant proteolytic degradation may therefore play a major role in neuronal degeneration. Indeed, the linkage of two genes directly involved in the ubiquitin-proteasome system (UPS) in familial Parkinson's disease clearly indicates a central role for the UPS in neurodegeneration, and thus Parkinson's disease is considered the prototypical disorder associated with UPS dysfunction. In this review, we provide an overview of the key genes/proteins implicated in the abnormal UPS-mediated proteolytic processing of unwanted proteins observed in neurodegenerative brain amyloidoses. We also provide an outline of the various components and pathways involved in the normal cellular functioning of the UPS and discuss the mechanisms by which UPS dysfunction can compromise neuronal integrity. A more complete understanding of the UPS and its relationship to the neurodegenerative process will undoubtedly provide tremendous insight into the molecular pathogenesis of amyloidogenic neurodegenerative disorders and will allow the development of novel rational therapies for treating these disorders.

Lim KL, Dawson VL, Dawson TM. · Neurodegeneration Research Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433. · Ann N Y Acad Sci. · Pubmed #12846976 No free full text.

Abstract: Parkinson's Disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 (UCHL1). All three PD-linked gene products are related directly or indirectly to the functioning of the cellular ubiquitin proteasomal system (UPS), suggesting that UPS dysfunction may be important in PD pathogenesis. Indeed, emerging evidence indicates that derangements of the UPS may be one of the underlying mechanisms of PD pathogenesis. The function of parkin as an ubiquitin protein ligase positions it as an important player in both familial and idiopathic PD. We recently demonstrated that parkin mediates a nondegradative form of ubiquitination on synphilin-1 that could contribute to synphilin-1's aggregation in PD. Our results implicate parkin involvement in the formation of Lewy bodies associated with sporadic PD. This review discusses the role of the UPS, as well as the modus operandi of the three PD candidate felons (alpha-synuclein, parkin, and UCHL1) along with their conspirators in bringing about dopaminergic cell death in PD.

Dawson TM, Dawson VL. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · J Clin Invest. · Pubmed #12531866 links to  free full text

This publication has no abstract.

Dawson TM, Dawson VL. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Nat Neurosci. · Pubmed #12403986 No free full text.

Abstract: Advances in understanding the molecular mechanisms of cell death and the pathogenesis of sporadic and familial Parkinson's disease are creating new opportunities for the development of neuroprotective and/or neurorestorative therapies. Here we review many of these advances, highlighting areas and strategies that might be particularly suited to the development of innovative approaches that prevent degeneration and/or restore function in Parkinson's disease.

Lim KL, Dawson VL, Dawson TM. · Department of Neurology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Carnegie 214, Baltimore, MD 21287, USA. · Curr Neurol Neurosci Rep. · Pubmed #12169225 No free full text.

Abstract: The recent identification of several genes and gene loci linked to familial forms of Parkinson's disease (PD) has contributed significantly to our understanding of the genetic contribution in PD. Although the etiology of sporadic PD remains unknown, it is currently assumed that genetic susceptibilities may be involved. The advent of genome-wide scanning techniques has now made it possible to conduct complete genome screens for linkage in PD in multigenerational parkinsonian kindreds. Such studies undoubtedly will be instrumental in establishing the susceptibility genes involved in idiopathic PD. This article reviews the recent advances in the genetics of PD.

Chung KK, Dawson VL, Dawson TM. · Dept of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Trends Neurosci. · Pubmed #11881748 No free full text.

Abstract: A unifying feature of neurodegenerative diseases is the abnormal accumulation and processing of mutant or damaged intra- and extracellular proteins; this leads to selective neuronal vulnerability and dysfunction. The ubiquitin-proteasomal pathway (UPP) is poised to play a central role in the processing of damaged and toxic proteins by ubiquitin-dependent proteolysis. The UPP can be overwhelmed in several neurodegenerative diseases. This results in the accumulation of toxic proteins and the formation of inclusions, and ultimately to neuronal dysfunction and cell death. Further analysis of the cellular and molecular mechanisms by which the UPP influences the detoxification of damaged and toxic proteins in neurodegenerative diseases could provide novel concepts and targets for the treatment and understanding of the pathogenesis of these devastating disorders.

Zhang Y, Dawson VL, Dawson TM. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA. · Neurobiol Dis. · Pubmed #10964596 No free full text.

Abstract: Parkinson's Disease (PD) is the second most common chronic neurodegenerative disease characterized by the progressive loss of dopamine neurons, leading to rigidity, slowness of movement, rest tremor, gait disturbances, and imbalance. Although there is effective symptomatic treatment for PD, there is no proven preventative or regenerative therapy. The etiology of this disorder remains unknown. Recent genetic studies have identified mutations in alpha-synuclein as a rare cause of autosomal dominant familial PD and mutations in parkin as a cause of autosomal recessive familial PD. The more common sporadic form of PD is thought to be due to oxidative stress and derangements in mitochondrial complex I activity. Understanding the mechanism by which familial linked mutations and oxidative stress cause PD has tremendous potential for unraveling the mechanisms of dopamine cell death in PD. In this article, we review recent advances in the understanding of the role of genetics and oxidative stress in the pathogenesis of PD.

Tsang AH, Lee YI, Ko HS, Savitt JM, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM, Chung KK. · Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong. · Proc Natl Acad Sci U S A. · Pubmed #19273858 No free full text.

Abstract: Inhibitors of apoptosis (IAPs) are a family of highly-conserved proteins that regulate cell survival through binding to caspases, the final executioners of apoptosis. X-linked IAP (XIAP) is the most widely expressed IAP and plays an important function in regulating cell survival. XIAP contains 3 baculoviral IAP repeats (BIRs) followed by a RING finger domain at the C terminal. The BIR domains of XIAP possess anticaspase activities, whereas the RING finger domain enables XIAP to function as an E3 ubiquitin ligase in the ubiquitin and proteasomal system. Our previous study showed that parkin, a protein that is important for the survival of dopaminergic neurons in Parkinson's disease (PD), is S-nitrosylated both in vitro and in vivo in PD patients. S-nitrosylation of parkin compromises its ubiquitin E3 ligase activity and its protective function, which suggests that nitrosative stress is an important factor in regulating neuronal survival during the pathogenesis of PD. In this study we show that XIAP is S-nitrosylated in vitro and in vivo in an animal model of PD and in PD patients. Nitric oxide modifies mainly cysteine residues within the BIR domains. In contrast to parkin, S-nitrosylation of XIAP does not affect its E3 ligase activity, but instead directly compromises its anticaspase-3 and antiapoptotic function. Our results confirm that nitrosative stress contributes to PD pathogenesis through the impairment of prosurvival proteins such as parkin and XIAP through different mechanisms, indicating that abnormal S-nitrosylation plays an important role in the process of neurodegeneration.

Ko HS, Bailey R, Smith WW, Liu Z, Shin JH, Lee YI, Zhang YJ, Jiang H, Ross CA, Moore DJ, Patterson C, Petrucelli L, Dawson TM, Dawson VL. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Proc Natl Acad Sci U S A. · Pubmed #19196961 No free full text.

Abstract: Mutation in leucine-rich repeat kinase-2 (LRRK2) is the most common cause of late-onset Parkinson's disease (PD). Although most cases of PD are sporadic, some are inherited, including those caused by LRRK2 mutations. Because these mutations may be associated with a toxic gain of function, controlling the expression of LRRK2 may decrease its cytotoxicity. Here we show that the carboxyl terminus of HSP70-interacting protein (CHIP) binds, ubiquitinates, and promotes the ubiquitin proteasomal degradation of LRRK2. Overexpression of CHIP protects against and knockdown of CHIP exacerbates toxicity mediated by mutant LRRK2. Moreover, HSP90 forms a complex with LRRK2, and inhibition of HSP90 chaperone activity by 17AAG leads to proteasomal degradation of LRRK2, resulting in increased cell viability. Thus, increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2. These findings point to potential treatment options for LRRK2-associated PD.

Moore DJ, West AB, Dikeman DA, Dawson VL, Dawson TM. · Institute for Cell Engineering, and Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. · J Neurochem. · Pubmed #18248624 No free full text.

Abstract: Mutations in the parkin gene cause autosomal recessive, juvenile-onset parkinsonism. Parkin is an E3 ubiquitin ligase that mediates the ubiquitination of protein substrates. Disease-associated mutations cause a loss-of-function of parkin which may compromise the poly-ubiquitination and proteasomal degradation of specific protein substrates, potentially leading to their deleterious accumulation. Here, we identify the molecular chaperones, Hsp70 and Hsc70, as substrates for parkin. Parkin mediates the ubiquitination of Hsp70 both in vitro and in cultured cells. Parkin interacts with Hsp70 via its second RING finger domain and mutations in/near this domain compromise Hsp70 ubiquitination. Ubiquitination of Hsp70 fails to alter its steady-state levels or turnover, nor does it promote its proteasomal degradation. Consistent with this observation, Hsp70 levels remain unaltered in brains from parkin-deficient autosomal recessive, juvenile-onset parkinsonism subjects, whereas alternatively, Hsp70 levels are elevated in the detergent-insoluble fraction of sporadic Parkinson's disease/dementia with Lewy bodies brains. Parkin mediates the multiple mono-ubiquitination of Hsp70/Hsc70 consistent with a degradation-independent role for this ubiquitin modification. Our observations support a novel functional relationship between parkin and Hsc/Hsp70 and support the notion that parkin is a multi-purpose E3 ubiquitin ligase capable of modifying proteins either via attachment of alternatively linked poly-ubiquitin chains or through multiple mono-ubiquitination to achieve alternate biological outcomes.

Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S, Dawson TM, Dawson VL. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD 21205, USA. · Proc Natl Acad Sci U S A. · Pubmed #17766438 links to  free full text

Abstract: Parkinson's disease (PD) is a common neurodegenerative movement disorder. Whereas the majority of PD cases are sporadic, rare genetic defects have been linked to this prevalent movement disorder. Mutations in DJ-1 are associated with autosomal recessive early-onset PD. The exact biochemical function of DJ-1 has remained elusive. Here we report the generation of DJ-1 knockout (KO) mice by targeted deletion of exon 2 and exon 3. There is no observable degeneration of the central dopaminergic pathways, and the mice are anatomically and behaviorally similar to WT mice. Fluorescent Amplex red measurements of H(2)O(2) indicate that isolated mitochondria from young and old DJ-1 KO mice have a 2-fold increase in H(2)O(2). DJ-1 KO mice of 2-3 months of age have a 60% reduction in mitochondrial aconitase activity without compromising other mitochondrial processes. At an early age there are no differences in antioxidant enzymes, but in older mice there is an up-regulation of mitochondrial manganese superoxide dismutase and glutathione peroxidase and a 2-fold increase in mitochondrial glutathione peroxidase activity. Mutational analysis and mass spectrometry reveal that DJ-1 is an atypical peroxiredoxin-like peroxidase that scavenges H(2)O(2) through oxidation of Cys-106. In vivo there is an increase of DJ-1 oxidized at Cys-106 after 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine intoxication of WT mice. Taken together these data indicate that the DJ-1 KO mice have a deficit in scavenging mitochondrial H(2)O(2) due to the physiological function of DJ-1 as an atypical peroxiredoxin-like peroxidase.

Wong ES, Tan JM, Wang C, Zhang Z, Tay SP, Zaiden N, Ko HS, Dawson VL, Dawson TM, Lim KL. · Neurodegeneration Research Laboratory and Parkinson's Disease and Movement Disorders Center, National Neuroscience Institute, Singapore 308433. · J Biol Chem. · Pubmed #17329252 links to  free full text

Abstract: Loss of parkin function is a predominant cause of familial Parkinsonism. Emerging evidence also suggests that parkin expression variability may confer a risk for sporadic Parkinson disease. We have recently demonstrated that a wide variety of Parkinson disease-linked stressors, including dopamine (DA), induce parkin solubility alterations and promote its aggregation within the cell, a phenomenon that may underlie the progressive susceptibility of the brain to degeneration. The vulnerability of parkin to stress-induced modification is likely due to its abundance of cysteine residues. Here, we performed a comprehensive mutational analysis and demonstrate that Cys residues residing both within and outside of the RING-IBR (in between RING fingers)-RING domain of parkin are important in maintaining its solubility. The majority of these Cys residues are highly conserved in parkin across different species and potentially fulfil important structural roles. Further, we found that both parkin and HHARI (human homologue of Drosophila ariadne), another RING-IBR-RING-type ubiquitin ligase, are comparably more susceptible to solubility alterations induced by oxidative and nitrosative stress when compared with other non-RING-IBR-RING Cys-containing enzymes. However, parkin appears to be uniquely sensitive to DA-mediated stress, the specificity of which is likely due to DA modification of 2 Cys residues on parkin (Cys-268 and Cys-323) that are distinct from other RING-IBR-RING members.