Parkinson Disease: Burke RE

Burke RE, Dauer WT, Vonsattel JP. · Department of Neurology, Columbia University Medical Center, New York, NY, USA. · Ann Neurol. · Pubmed #19067353 No free full text.

Abstract: Braak and colleagues have proposed that, within the central nervous system, Parkinson's disease (PD) begins as a synucleinopathy in nondopaminergic structures of the lower brainstem or in the olfactory bulb. The brainstem synucleinopathy is postulated to progress rostrally to affect the substantia nigra and cause parkinsonism at a later stage of the disease. In the context of a diagnosis of PD, made from current clinical criteria, the pattern of lower brainstem involvement accompanying mesencephalic synucleinopathy is often observed. However, outside of that context, the patterns of synucleinopathy that Braak described are often not observed, particularly in dementia with Lewy bodies and when synucleinopathy occurs in the absence of neurological manifestations. The concept that lower brainstem synucleinopathy represents "early PD" rests on the supposition that it has a substantial likelihood of progressing within the human lifetime to involve the mesencephalon, and thereby cause the substantia nigra pathology and clinical parkinsonism that have heretofore defined the disease. However, the predictive validity of this concept is doubtful, based on numerous observations made in populations of aged individuals who, despite the absence of neurological signs, have brain synucleinopathy ranging up to Braak stages 4 to 6 at postmortem. Furthermore, there is no relation between Braak stage and the clinical severity of PD. We conclude that the relation between patterns of abnormal synuclein immunostaining in the human brain and the disease entity now recognized as PD remains to be determined.

Kuan CY, Burke RE. · Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA. · Curr Drug Targets CNS Neurol Disord. · Pubmed #15723614 No free full text.

Abstract: The c-Jun NH2-terminal Kinase (JNK) signaling pathway is frequently induced by cellular stress and correlated with neuronal death. This unique property makes JNK signaling a promising target for developing pharmacological intervention. Among several neurological disorders, JNK signaling is particularly implicated in ischemic stroke and Parkinson's disease. The inhibitors of the JNK signaling pathway include upstream kinase inhibitors (for example, CEP-1347), small chemical inhibitors of JNK (SP600125 and AS601245), and peptide inhibitors of the interaction between JNK and its substrates (D-JNKI and I-JIP). The mechanisms by which JNK signaling induces apoptosis and evidence of cytoprotective effects of these JNK inhibitors are summarized in the present review.

Silva RM, Kuan CY, Rakic P, Burke RE. · Department of Neurology, The College of Physicians and Surgeons, Columbia University, 650 West 168th Street, New York, NY 10032, USA. · Mov Disord. · Pubmed #15719422 No free full text.

Abstract: There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) -c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway.

Burke RE. · Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Neurologist. · Pubmed #14998437 No free full text.

Abstract: BACKGROUND: Until recently, most research effort on Parkinson disease (PD) was focused on possible environmental causes. With the discovery of mutations in two genes, synuclein and parkin, which are responsible for rare familial forms of the disease, there has been a major change in emphasis. REVIEW SUMMARY: The first genetic cause of PD to be identified was in the gene for synuclein, resulting in an alanine to threonine substitution at position 53. The likely pathogenetic significance of this mutation was supported by the discovery of a second mutation, and the presence of synuclein in Lewy bodies in sporadic PD cases. The synuclein protein has a tendency to self aggregate, and this tendency is increased in the mutants, and by oxidative injury to the protein. While there is growing evidence in animal models that overexpression of wildtype or mutant synuclein may lead to intracytoplasmic inclusions, and dysfunction of dopamine neurons, no animal models in rodents have yet replicated all important features of the disease. Deletions or point mutations in the gene for parkin cause an autosomal recessive, early onset form of parkinsonism. The parkin protein functions as an E3 ubiquitin-protein ligase, and it is involved in the degradation of cellular proteins by the proteasomal pathway. It is hypothesized that the loss of this function results in the toxic accumulation of its target proteins. CONCLUSIONS: Research on these inherited forms of PD is pointing towards a common theme, that disturbances of cellular protein handling can lead to the death of dopamine neurons in PD.

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.

Ries V, Henchcliffe C, Kareva T, Rzhetskaya M, Bland R, During MJ, Kholodilov N, Burke RE. · Department of Neurology, Columbia University College of Physicians and Surgeons, 650 West 168th Street, New York, NY 10032, USA. · Proc Natl Acad Sci U S A. · Pubmed #17116866 links to  free full text

Abstract: Despite promising preclinical studies, neurotrophic factors have not yet achieved an established role in the treatment of human neurodegenerative diseases. One impediment has been the difficulty in providing these macromolecules in sufficient quantity and duration at affected sites. An alternative approach is to directly activate, by viral vector transduction, intracellular signaling pathways that mediate neurotrophic effects. We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB. Adeno-associated virus Myr-Akt has pronounced trophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, phenotypic markers, and sprouting. Transduction confers almost complete protection against apoptotic cell death in a highly destructive neurotoxin model. Activation of intracellular neurotrophic signaling pathways by vector transfer is a feasible approach to neuroprotection and restorative treatment of neurodegenerative disease.

Stefanis L, Wang Q, Oo T, Lang-Rollin I, Burke RE, Dauer WT. · Department of Neurology, Columbia University, New York, NY, USA. · Eur J Neurosci. · Pubmed #15380020 No free full text.

Abstract: alpha-Synuclein is an abundant neuronal protein of uncertain function linked to Parkinson's disease. Numerous studies have proposed an antiapoptotic function for alpha-synuclein, based on overexpression experiments in cell lines. To explore whether alpha-synuclein has such a physiological function, we assessed the response of wild type or alpha-synuclein null neonatal mouse sympathetic neurons to nerve growth factor deprivation, a well-characterized stimulus of neuronal apoptosis. There was no difference in the rate of neuronal loss, neuronal apoptosis, or c-jun phosphorylation. Furthermore, the absence of alpha-synuclein did not alter the magnitude of naturally occurring cell death in vivo in substantia nigra pars compacta. Therefore, alpha-synuclein is unlikely to play a significant role in apoptotic signalling in catecholaminergic neurons of the neonatal nervous system.

Oo TF, Siman R, Burke RE. · Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. · Exp Neurol. · Pubmed #12009755 No free full text.

Abstract: An emerging theme in programmed cell death (PCD) of neurons is that the mechanisms involved depend on the cellular context and the death-inducing stimulus. One particular class of neurons for which it is important to identify the mechanisms of PCD are the dopamine neurons of the substantia nigra, the neurons which degenerate in Parkinson's disease. PCD has been shown to occur in these neurons during normal development and to be induced in neurotoxin models of parkinsonism. Conventional histologic stains and TUNEL labeling have not revealed morphologic differences in the apoptosis observed in these neurons in any context. We now show that in two models of induced PCD in postmitotic dopamine neurons, one induced by early striatal target injury and another induced by the neurotoxin 6-hydroxydopamine (6OHDA), there are differences in the cellular localization and type of caspase cleavage products. Using two antibodies to caspase cleavage products (fractin and AB127), we show that in the target lesion model immunostaining is localized to the nucleus, whereas in the 6OHDA model intense cytoplasmic as well as nuclear staining is observed. Another antibody, AB246, to a caspase cleavage product of spectrin, immunostains apoptotic profiles only in the 6OHDA model. These findings suggest that the cellular compartment and therefore the role of the caspases may differ in apoptosis induced in pathologic settings, such as that due to neurotoxins, from that observed in models of natural or induced natural cell death. It will be important to recognize these differences in the consideration of caspase inhibitors in the treatment of degenerative neurologic disease.

Burke RE. · Department of Neurology, Columbia University, New York City, NY 10032, USA. · Lancet. · Pubmed #11716878 No free full text.

This publication has no abstract.

Jackson-Lewis V, Vila M, Djaldetti R, Guegan C, Liberatore G, Liu J, O'Malley KL, Burke RE, Przedborski S. · Neuroscience Research, Movement Disorder Division, Department of Neurology, Columbia University, New York, New York 10032, USA. · J Comp Neurol. · Pubmed #10906714 No free full text.

Abstract: Dopaminergic neurons in the substantia nigra pars compacta (SNpc) undergo natural cell death during development in rats. Controversy exists as to the occurrence of this phenomenon in SNpc dopaminergic neurons in the developing mouse. Herein, by using an array of morphologic techniques, we show that many SNpc neurons fulfill the criteria for apoptosis and that the number of apoptotic neurons in the SNpc vary in a time-dependent manner from postnatal day 2 to 32. These dying neurons also show evidence of DNA fragmentation, of activated caspase-3, and of cleavage of beta-actin. Some, but not all of the SNpc apoptotic neurons still express their phenotypic marker tyrosine hydroxylase, confirming their dopaminergic nature. Consistent with the importance of target-derived trophic support in modulating developmental cell death, we demonstrate that destruction of intrinsic striatal neurons by a local injection of quinolinic acid (QA) dramatically enhances the magnitude of SNpc apoptosis and results in a lower number of adult SNpc dopaminergic neurons. Strengthening the apoptotic nature of the observed SNpc developmental cell death, we demonstrate that overexpression of the anti-apoptotic protein Bcl-2 attenuates both natural and QA-induced SNpc apoptosis. The present study provides compelling evidence that developmental neuronal death with a morphology of apoptosis does occur in the SNpc of mice and that this process plays a critical role in regulating the adult number of dopaminergic neurons in the SNpc.

Burke RE. · Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. · Brain Res Bull. · Pubmed #10643486 No free full text.

This publication has no abstract.

Kholodilov NG, Neystat M, Oo TF, Lo SE, Larsen KE, Sulzer D, Burke RE. · Department of Neurology, New York State Psychiatric Institute, Columbia University, College of Physicians and Surgeons, New York 10032, USA. · J Neurochem. · Pubmed #10582622 No free full text.

Abstract: Human alpha-synuclein was identified on the basis of proteolytic fragments derived from senile plaques of Alzheimer's disease, and it is the locus of mutations in some familial forms of Parkinson's disease. Its normal function and whether it may play a direct role in neural degeneration remain unknown. To explore cellular responses to neural degeneration in the dopamine neurons of the substantia nigra, we have developed a rodent model of apoptotic death induced by developmental injury to their target, the striatum. We find by mRNA differential display that synuclein is up-regulated in this model, and thus it provides an opportunity to examine directly whether synuclein plays a role in the death of these neurons or, alternatively, in compensatory responses. Up-regulation of mRNA is associated with an increase in the number of neuronal profiles immunostained for synuclein protein. At a cellular level, synuclein is almost exclusively expressed in normal neurons, rather than apoptotic profiles. Synuclein is up-regulated throughout normal postnatal development of substantia nigra neurons, but it is not further up-regulated during periods of natural cell death. We conclude that up-regulation of synuclein in the target injury model is unlikely to mediate apoptotic death and propose that it may be due to a compensatory response in neurons destined to survive.

Neystat M, Lynch T, Przedborski S, Kholodilov N, Rzhetskaya M, Burke RE. · Department of Neurology, College of Physicians & Surgeons, Columbia University, Columbia-Presbyterian Medical Center, New York, NY 10032, USA. · Mov Disord. · Pubmed #10348463 No free full text.

Abstract: Mutations in the human alpha-synuclein gene have been identified in several families of European descent with early-onset Parkinson's disease (PD). We sequenced the complete alpha-synuclein cDNA from substantia nigra and cortex from nine patients with PD and eight control subjects. No mutations were found. We then analyzed alpha-synuclein mRNA levels using a ribonuclease protection assay. Two major protected bands of alpha-synuclein mRNA, possibly representing two splice variants of the gene, were observed. Alpha-synuclein mRNA was significantly diminished in the substantia nigra of patients with PD compared with control subjects but not in the cortex. Our findings suggest that decreased synuclein mRNA may be an early alteration in the SN in PD, and imply that decreased levels of the protein may play a role in the pathogenesis of sporadic cases of the disease.

Oo TF, Henchcliffe C, James D, Burke RE. · Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. · J Neurochem. · Pubmed #9930727 No free full text.

Abstract: The transcription factors c-fos and c-jun have been proposed to play a role in the initiation of programmed cell death in neurons. We have shown that programmed cell death, with the morphology of apoptosis, occurs in dopamine neurons of the substantia nigra (SN) during normal postnatal development and that this death event can be induced by early striatal target injury. We have investigated the relationship between c-fos and c-jun protein expression and induced death in neurons of the SN. Although c-fos is induced, it is unlikely to play a role in cell death, because its expression is not well correlated with apoptotic death either temporally or at a cellular level. Expression of c-jun, however, is both temporally and regionally correlated with induction of death, and, at a cellular level, it colocalizes with apoptotic morphology. The increased expression of c-jun is likely to be functionally significant, because it is associated with increased c-jun N-terminal kinase (JNK) and phosphorylated c-jun expression. JNK expression also colocalizes with apoptotic morphology. We conclude that c-jun is likely to play a role in the initiation of apoptotic cell death in these neurons.