Parkinson Disease: Przedborski S

Zhou C, Huang Y, Przedborski S. · Department of Neurology, Columbia University, New York, NY 10032, USA. · Ann N Y Acad Sci. · Pubmed #19076434 No free full text.

Abstract: Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, time-course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death-related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.

Bové J, Prou D, Perier C, Przedborski S. · Department of Neurology, Columbia University, New York, New York 10032, USA. · NeuroRx. · Pubmed #16389312 links to  free full text

Abstract: Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.

Przedborski S, Ischiropoulos H. · Department of Neurology, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA. · Antioxid Redox Signal. · Pubmed #15890013 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disease whose etiology and pathogenesis remain mainly unknown. To investigate its cause and, more particularly, its mechanism of neuronal death, numerous in vivo experimental models have been developed. Currently, both genetic and toxic models of PD are available, but the use of neurotoxins such as 6-hydroxydopamine, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and rotenone are still the most popular means for modeling the destruction of the nigrostriatal dopaminergic neurons seen in PD. These four neurotoxins, although distinct in their intimate cytotoxic mechanisms, kill dopaminergic neurons via a cascade of deleterious events that consistently involves oxidative stress. Herein, we review and compare the molecular mechanisms of 6-hydroxydopamine, paraquat, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, and rotenone, placing the emphasis of our discussion on how reactive oxygen and nitrogen species contribute to the neurotoxic properties of these four molecules. As the reader will discover, to achieve the above stated goal, we had to not only appraise recent findings, but also revisit earlier landmark studies to provide a comprehensive view on this topic. This approach also enabled us to describe how our understanding of the mechanism of actions of certain toxins has evolved over time, which is particularly striking in the case of the quatrogenarian neurotoxin, 6-hydroxydopamine.

Przedborski S. · Departmentsof Neurology, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA. · Parkinsonism Relat Disord. · Pubmed #15885625 No free full text.

Abstract: Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.

Eriksen JL, Przedborski S, Petrucelli L. · Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA. · Trends Mol Med. · Pubmed #15760766 No free full text.

Abstract: Four recent papers related specifically to the familial form of Parkinson's disease reinforce the idea that endogenous levels of alpha-synuclein can strongly influence disease phenotype. Two recent publications of alpha-synuclein-duplication mutations show that the severity of familial Parkinsonian phenotype is dependent upon SNCA gene dosage and corresponding protein levels. Familial point mutations in SNCA were found to impair the efficient lysosomal degradation of alpha-synuclein, potentially resulting in elevated levels of alpha-synuclein. Conversely, the complete knockout of SNCA has little effect on transgenic mice. It is now clear that the regulation of alpha-synuclein levels has potential significance in the pathogenesis and treatment of sporadic PD.

Vila M, Przedborski S. · Department of Neurology, Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA. · Nat Med. · Pubmed #15272270 No free full text.

Abstract: Recent years have seen an explosion in the rate of discovery of genetic defects linked to Parkinson's disease. These breakthroughs have not provided a direct explanation for the disease process. Nevertheless, they have helped transform Parkinson's disease research by providing tangible clues to the neurobiology of the disorder.

Dauer W, Przedborski S. · Department of Neurology, Columbia University, New York, NY 10032, USA. · Neuron. · Pubmed #12971891 No free full text.

Abstract: Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.

Tieu K, Ischiropoulos H, Przedborski S. · Department of Neurology, Columbia University, New York, NY 10032, USA. · IUBMB Life. · Pubmed #12938735 No free full text.

Abstract: Parkinson's disease is a neurodegenerative disorder of unknown pathogenesis. Oxidative stress has been proposed as one of several pathogenic hypotheses. Evidence for the participation of oxidative processes in the pathogenesis of Parkinson's disease have been obtained in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model by the use of genetically altered mice. MPTP administration has been shown to increase levels of superoxide both intracellularly, via the inhibition of mitochondrial respiration and other mechanisms and extracellularly, via the activation of NADPH-oxidase in microglia. In addition to superoxide, nitric oxide production by nNOS or by microglial iNOS also contributes to the MPTP neurotoxocity. Mice with endowed defences against superoxide or with deficiency in the nNOS and iNOS are protected from MPTP toxicity suggesting that formation of reactive oxygen and nitrogen intermediates both intracellularly and extracellularly contributes to the demise of dopaminergic neurons. Similar contribution of reactive nitrogen and oxygen species may well underlie the neurodegenerative processes in Parkinson's disease.

Teismann P, Vila M, Choi DK, Tieu K, Wu DC, Jackson-Lewis V, Przedborski S. · Neuroscience Research Laboratories of the Movement Disorder Division, Department of Neurology, Columbia University, New York, New York 10032, USA. · Ann N Y Acad Sci. · Pubmed #12846993 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Recent observations link cyclooxygenase type-2 (COX-2) to the progression of the disease. Consistent with this notion, studies with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) show that inhibition and ablation of COX-2 markedly reduce the deleterious effects of this toxin on the nigrostriatal pathway. The similarity between this experimental model and PD strongly supports the possibility that COX-2 expression is also pathogenic in PD.

Vila M, Przedborski S. · Department of Neurology, Columbia University, 650 West 168th Street, BB-307, New York, New York 10032, USA. · Nat Rev Neurosci. · Pubmed #12728264 No free full text.

This publication has no abstract.

Wu DC, Tieu K, Cohen O, Choi DK, Vila M, Jackson-Lewis V, Teismann P, Przedborski S. · Neuroscience Research, Movement Disorder Division, Department of Neurology, Columbia University, New York, New York, USA. · J Neurovirol. · Pubmed #12476349 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, proinflammatory prostaglandin, and cytokines. In this review, the authors discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how these factors may contribute to the pathogenesis of this disease.

Vila M, Wu DC, Przedborski S. · Dept Neurology, Columbia University, New York, NY 10032, USA. · Trends Neurosci. · Pubmed #11881746 No free full text.

Abstract: The development of new methods for manipulating the animal genome by transgenic and gene-targeting technologies provides a unique means of studying the most intimate aspects of countless human diseases, including Parkinson's disease (PD). In this review, the contribution of such engineered models to our current understanding of the pathophysiology, etiology and pathogenesis of PD will be discussed.

Przedborski S, Vila M. · Department of Neurology and Department of Pathology, Columbia University, New York, New York 10032, USA. · Adv Neurol. · Pubmed #11553976 No free full text.

This publication has no abstract.

Vila M, Jackson-Lewis V, Guégan C, Wu DC, Teismann P, Choi DK, Tieu K, Przedborski S. · Department of Neurology, Columbia University, New York, New York 10032, USA. · Curr Opin Neurol. · Pubmed #11470965 No free full text.

Abstract: Parkinson's disease is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta. The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Aside from these beneficial effects, the glial response can mediate a variety of deleterious events related to the production of reactive species, and pro-inflammatory prostaglandin and cytokines. This article reviews the potential protective and deleterious effects of glial cells in the substantia nigra pars compacta of Parkinson's disease.

Dhib-Jalbut S, Arnold DL, Cleveland DW, Fisher M, Friedlander RM, Mouradian MM, Przedborski S, Trapp BD, Wyss-Coray T, Yong VW. · UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, and The Cleveland Clinic, OH, USA. · J Neuroimmunol. · Pubmed #16983747 No free full text.

Abstract: Multiple sclerosis is considered a disease of myelin destruction; Parkinson's disease (PD), one of dopaminergic neuron depletion; ALS, a disease of motor neuron death; and Alzheimer's, a disease of plaques and tangles. Although these disorders differ in important ways, they also have common pathogenic features, including inflammation, genetic mutations, inappropriate protein aggregates (e.g., Lewy bodies, amyloid plaques), and biochemical defects leading to apoptosis, such as oxidative stress and mitochondrial dysfunction. In most disorders, it remains uncertain whether inflammation and protein aggregation are neurotoxic or neuroprotective. Elucidating the mechanisms that orchestrate neuronal diseases should facilitate development of neuroprotective and neurorestorative strategies.

Kostić VS, Marinković J, Svetel M, Stefanova E, Przedborski S. · Institute of Neurology CCS, Belgrade, Yugoslavia. · Eur J Neurol. · Pubmed #11784369 No free full text.

Abstract: The aim of this study was to ascertain whether the stage of Parkinson's disease (PD) (according to the Hoehn and Yahr staging system) would affect the length of time between the introduction of levodopa therapy and appearance of levodopa-associated motor complications. Forty patients with clinically definite PD were studied. In all, clinical and therapeutic data were collected from the time of diagnosis to the time of levodopa-associated motor complications (i.e. dyskinesia, motor fluctuations). In 17 patients, levodopa could be started in Hoehn and Yahr stage I (H & Y-I; 16.2 months after the onset of PD), whilst in 13 patients levodopa could be started in H & Y-II (19.6 months after the onset of the disease) and in 10 in H & Y-III (45.1 months after the onset of PD). Cox proportional hazard regression model shows that the PD patients in whom the initial levodopa treatment was introduced at stage III develop both dyskinesias and motor fluctuations significantly earlier than the patients whose levodopa started in stage I and II of PD. The median interval to develop dyskinesias was 66, 72 and 24 months for patients in whom levodopa was introduced in stage I, II and III, respectively. These values were 64, 55 and 14 months for motor fluctuations. These findings add to the clinical arguments that favour an essential role of severity of PD at levodopa initiation as a risk factor for the development of levodopa-associated motor complications.

Giladi N, McDermott MP, Fahn S, Przedborski S, Jankovic J, Stern M, Tanner C, Anonymous00234. · Movement Disorders Division, Department of Neurology, Columbia-Presbyterian Medical Center, New York, NY, USA. · Neurology. · Pubmed #11425939 No free full text.

Abstract: OBJECTIVE: To study the development of freezing of gait in PD. BACKGROUND: Freezing of gait is a common, disabling, and poorly understood symptom in PD. METHODS: The authors analyzed data from 800 patients with early PD from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) clinical trial who were assigned either placebo, deprenyl, tocopherol, or the combination of deprenyl and tocopherol. The primary outcome measure was the time from randomization until the freezing of gait score on the Unified Parkinson's Disease Rating Scale (UPDRS) became positive. RESULTS: Fifty-seven patients (7.1%) had freezing of gait at study entry and 193 (26%) of the remaining patients experienced the symptom by the end of the follow-up period. Those with freezing of gait at baseline had significantly more advanced disease than those without the symptom, as measured by total UPDRS and Hoehn and Yahr stage. High baseline risk factors for developing freezing of gait during the follow-up period were the onset of PD with a gait disorder; higher scores of rigidity, postural instability, bradykinesia and speech; and longer disease duration. In contrast, tremor was strongly associated with a decreased risk for freezing of gait. At the end of follow-up, the signs most strongly associated with the freezing phenomenon were gait, balance, and speech disorders, not rigidity or bradykinesia. Deprenyl treatment was strongly associated with a decreased risk for developing freezing of gait; tocopherol had no effect. CONCLUSIONS: Freezing of gait is directly related to duration of PD. Risk factors at onset of disease are the absence of tremor and PD beginning as a gait disorder. The development of freezing of gait in the course of the illness is strongly associated with the development of balance and speech problems, less so with the worsening of bradykinesia, and is not associated with the progression of rigidity. These results support the concept that the freezing phenomenon is distinct from bradykinesia. Deprenyl, in the absence of L-dopa, was found to be an effective prophylactic treatment and should be considered for patients with PD who have an onset of gait difficulty.

Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, Zhou C, Geghman K, Bogdanov M, Przedborski S, Beal MF, Burke RE, Li C. · Department of Neurology and Neurosciences, Weill Medical College of Cornell University, New York, New York, USA. · Nat Neurosci. · Pubmed #19503083 No free full text.

Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. We created a LRRK2 transgenic mouse model that recapitulates cardinal features of the disease: an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection. These mice provide a valid model of Parkinson's disease and are a resource for the investigation of pathogenesis and therapeutics.

Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM. · Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, New York, New York 10461, USA. · J Clin Invest. · Pubmed #18172548 links to  free full text

Abstract: Altered degradation of alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of Parkinson disease (PD). We have shown that alpha-syn can be degraded via chaperone-mediated autophagy (CMA), a selective lysosomal mechanism for degradation of cytosolic proteins. Pathogenic mutants of alpha-syn block lysosomal translocation, impairing their own degradation along with that of other CMA substrates. While pathogenic alpha-syn mutations are rare, alpha-syn undergoes posttranslational modifications, which may underlie its accumulation in cytosolic aggregates in most forms of PD. Using mouse ventral medial neuron cultures, SH-SY5Y cells in culture, and isolated mouse lysosomes, we have found that most of these posttranslational modifications of alpha-syn impair degradation of this protein by CMA but do not affect degradation of other substrates. Dopamine-modified alpha-syn, however, is not only poorly degraded by CMA but also blocks degradation of other substrates by this pathway. As blockage of CMA increases cellular vulnerability to stressors, we propose that dopamine-induced autophagic inhibition could explain the selective degeneration of PD dopaminergic neurons.

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.

Bové J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout HJ, Wu DC, Kordower JH, Petrucelli L, Przedborski S. · Department of Neurology, Columbia University, New York, NY, USA. · Ann Neurol. · Pubmed #16862585 No free full text.

Abstract: Impaired proteasome function is a potential mechanism for dopaminergic neuron degeneration. To model this molecular defect, we administered systemically the reversible lipophilic proteasome inhibitor, carbobenzoxy-L-isoleucyl-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI), to rodents. In contrast to a previous report, this approach failed to cause any detectable behavioral or neuropathological abnormality in either rats or mice. Although theoretically appealing, this specific model of Parkinson's disease appears to exhibit poor reproducibility.

Perier C, Tieu K, Guégan C, Caspersen C, Jackson-Lewis V, Carelli V, Martinuzzi A, Hirano M, Przedborski S, Vila M. · Department of Neurology, Columbia University, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #16365298 links to  free full text

Abstract: Dysfunction of mitochondrial complex I is a feature of human neurodegenerative diseases such as Leber hereditary optic neuropathy and Parkinson's disease. This mitochondrial defect is associated with a recruitment of the mitochondrial-dependent apoptotic pathway in vivo. However, in isolated brain mitochondria, complex I dysfunction caused by either pharmacological or genetic means fails to directly activate this cell death pathway. Instead, deficits of complex I stimulate intramitochondrial oxidative stress, which, in turn, increase the releasable soluble pool of cytochrome c within the mitochondrial intermembrane space. Upon mitochondrial permeabilization by the cell death agonist Bax, more cytochrome c is released to the cytosol from brain mitochondria with impaired complex I activity. Given these results, we propose a model in which defects of complex I lower the threshold for activation of mitochondrial-dependent apoptosis by Bax, thereby rendering compromised neurons more prone to degenerate. This molecular scenario may have far-reaching implications for the development of effective neuroprotective therapies for these incurable illnesses.

Ved R, Saha S, Westlund B, Perier C, Burnam L, Sluder A, Hoener M, Rodrigues CM, Alfonso A, Steer C, Liu L, Przedborski S, Wolozin B. · Department of Pharmacology, Boston University School of Medicine, Boston, Massachusetts 02118-2526, USA. · J Biol Chem. · Pubmed #16239214 links to  free full text

Abstract: How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing alpha-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-beta-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining d-beta-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.

Choi DK, Pennathur S, Perier C, Tieu K, Teismann P, Wu DC, Jackson-Lewis V, Vila M, Vonsattel JP, Heinecke JW, Przedborski S. · Department of Neurology, Columbia University, New York, New York 10032, USA. · J Neurosci. · Pubmed #16014720 links to  free full text

Abstract: Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.

Hunot S, Vila M, Teismann P, Davis RJ, Hirsch EC, Przedborski S, Rakic P, Flavell RA. · Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. · Proc Natl Acad Sci U S A. · Pubmed #14704277 links to  free full text

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.