Parkinson Disease: Massachusetts

Outeiro TF, Giorgini F. · Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, USA. · Biotechnol J. · Pubmed #16897706 No free full text.

Abstract: The high degree of conservation of cellular and molecular processes between the budding yeast Saccharomyces cerevisiae and higher eukaryotes have made it a valuable system for numerous studies of the basic mechanisms behind devastating illnesses such as cancer, infectious disease, and neurodegenerative disorders. Several studies in yeast have already contributed to our basic understanding of cellular dysfunction in both Huntington's and Parkinson's disease. Functional genomics approaches currently being undertaken in yeast may lead to novel insights into the genes and pathways that modulate neuronal cell dysfunction and death in these diseases. In addition, the budding yeast constitutes a valuable system for identification of new drug targets, both via target-based and non-target-based drug screening. Importantly, yeast can be used as a cellular platform to analyze the cellular effects of candidate compounds, which is critical for the development of effective therapeutics. While the molecular mechanisms that underlie neurodegeneration will ultimately have to be tested in neuronal and animal models, there are several distinct advantages to using simple model organisms to elucidate fundamental aspects of protein aggregation, amyloid toxicity, and cellular dysfunction. Here, we review recent studies that have shown that amyloid formation by disease-causing proteins and many of the resulting cellular deficits can be faithfully recapitulated in yeast. In addition, we discuss new yeast-based techniques for screening candidate therapeutic compounds for Huntington's and Parkinson's diseases.

Kalda A, Yu L, Oztas E, Chen JF. · Molecular Neuropharmacology Lab, Department of Neurology, Boston University Medical Center, Boston, MA 02118, USA. · J Neurol Sci. · Pubmed #16806272 No free full text.

Abstract: The adenosine A(2A) receptor has recently emerged as a leading non-dopaminergic therapeutic target for Parkinson's disease, largely due to the restricted distribution of the receptor in the striatum and the profound interaction between adenosine and dopamine receptors in brain. Two lines of research in particular have demonstrated the promise of the A(2A) receptor antagonists as novel anti-parkinsonian drugs. First, building on extensive preclinical animal studies, the A(2A) receptor antagonist KW6002 has demonstrated its potential to increase motor activity in PD patients of the advanced stage in a recent clinical phase IIB trial. Second, recently two prospective epidemiological studies of large cohorts have firmly established the inverse relationship between the consumption of caffeine (a non-specific adenosine antagonist) and the risk of developing PD. The potential neuroprotective effect of caffeine and A(2A) receptor antagonists in PD is further substantiated by the demonstration that pharmacological blockade (by caffeine or specific A(2A) antagonists) or genetic depletion of the A(2A) receptor attenuated dopaminergic neurotoxicity and neurodegeneration in animal models of PD. Moreover, A(2A) receptor antagonism-mediated neuroprotection goes beyond PD models and can be extended to a variety of other brain injuries induced by stroke, excitotoxicity and mitochondrial toxins. Intensive investigations are under way to dissect out common cellular mechanisms (such as A(2A) receptor modulation of neuroinflammation) which may underlie the broad spectrum of neuroprotection by A(2A) receptor inactivation in brain.

Shirzadi AA, Ghaemi SN. · Harvard South Shore Psychiatry Program, Brockton, MA, USA. · Harv Rev Psychiatry. · Pubmed #16787887 No free full text.

Abstract: In this article we examine the two major classes of side effects with atypical antipsychotics: extrapyramidal symptoms (EPS) and the metabolic syndrome (the triad of diabetes, dyslipidemia, and hypertension, with associated obesity). We conclude that atypical antipsychotics continue to have notable risks of EPS, particularly akathisia, and that these agents also appear to increase the risk of the metabolic syndrome, though this effect seems most marked with clozapine and olanzapine. Novel conclusions based on this review are as follows: we provide a classification scheme based on low versus high D2 binding affinity (which is, to our knowledge, a new means of classifying atypical antipsychotics); we emphasize that the akathisia risk is likely equal among agents and that tardive dyskinesia is an early, and not late, risk in treatment (a common misconception); we make the methodological point that in randomized clinical trials, there is a high risk of false-negatives regarding side effects; we raise the issue of confounding bias in epidemiological studies of metabolic syndrome; and we stress the need to compare side effects in the same studies and not different studies. Future prospective observational cohort studies must target side effects and be designed to collect and analyze data on confounding factors.

McNamara P, Durso R. · Department of Neurology, Boston University School of Medicine, Boston VA Healthcare System, Boston, MA 02130, USA. · Behav Neurol. · Pubmed #16720959 No free full text.

Abstract: Many patients with Parkinson's Disease (PD) experience significant cognitive and mood impairment -even early in the course of the disease. These mental impairments are only partially responsive to levodopa treatment and are often as disabling as the motor impairment, particularly in mid and late stages of the disease. Investigators have recently begun a search for new agents that can effectively treat mental dysfunction of PD. Although there have been only a handful of properly controlled clinical trials of interventions targeted at amelioration of mental dysfunction in PD, progress has been made. Based on the available evidence, targeting catecholaminergic and cholinergic function may be an effective strategy for amelioration of cognitve, mood and psychiatric disturbances in PD.

Schernhammer E, Chen H, Ritz B. · Department of Medicine, Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · Cancer Causes Control. · Pubmed #16596313 No free full text.

Abstract: Lower rates of cancer mortality/incidence in patients with Parkinson's disease (PD) have given rise to speculations about risk or preventative factors common to both diseases, including life-style factors (such as smoking) and genetic susceptibility. Melatonin, a hormone known for its sleep regulatory effects, may play an important role in carcinogenesis as suggested by substantial laboratory and less direct epidemiologic evidence. Particularly, a reduction in melatonin, such as experienced by persons who are exposed to light at night, appears to increase cancer risk. Variations in melatonin levels have been linked to PD in several different ways. Some studies show higher morning melatonin levels in PD patients than in healthy controls. One could speculate that the sleep disorders that affect almost two thirds of those suffering from PD and can precede PD motor symptoms by several years may be associated with variations in melatonin levels. Moreover, in animal models, interventions that increase the bioavailability of melatonin appears to increase the severity of parkinsonian symptoms, whereas reduction in melatonin by pinealectomy or exposure to bright light can enhance recovery from parkinsonisms symptoms. Finally, preliminary epidemiological evidence suggests that longer years of working night shifts is associated with a reduced risk of PD among participants of the Nurses' Health Study (NHS), whereas longer hours of sleep appear to increase their risk. In sum, while lower melatonin concentrations may predict a higher cancer risk, there is also some evidence that they may be associated with a lower risk of PD. We therefore hypothesize that elevated circulating melatonin levels in PD patients may contribute to their lower cancer rates.

Bertram L, Hsiao M, McQueen MB, Parkinson M, Mullin K, Blacker D, Tanzi RE. · Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. · Neurobiol Aging. · Pubmed #16378661 No free full text.

Abstract: Genetic linkage studies suggest the presence of an Alzheimer's disease (AD) risk gene on chromosome 19, acting independently of apolipoprotein E (apoE), a known AD risk factor on 19q13. The low density lipoprotein receptor (LDLR) is an interesting candidate because it maps within the linked interval, and is intimately involved in cholesterol homeostasis and the function of apoE. We tested three previously reported single nucleotide polymorphisms (SNPs) within LDLR in a large sample of discordant sibships from multiplex AD families, and failed to find evidence for genetic association with disease risk. In addition, we performed meta-analyses for SNP rs5925 on published data from five independent case control samples, but did not detect any significant summary odds ratios. Based on our data, it seems unlikely that these genetic variants in LDLR make a significant contribution to AD risk in the general population.

Fregni F, Simon DK, Wu A, Pascual-Leone A. · Harvard Center for Noninvasive Brain Stimulation, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #16291882 links to  free full text

Abstract: A systematic review and meta-analysis were conducted to quantify the efficacy of transcranial magnetic stimulation (TMS) and electroconvulsive therapy (ECT) for the treatment of motor dysfunction in patients with Parkinson's disease (PD). Prospective studies which evaluated the effects of either TMS (12 studies) or ECT (five studies) on motor function in PD using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) for TMS studies and any continuous measures of motor function in PD for ECT studies were included. The pooled effect size (standardised mean difference between pre-treatment versus post-treatment means) from a random effects model was 0.62 (95% confidence interval: 0.38, 0.85) for TMS treatment and 1.68 (0.79, 2.56) for ECT treatment, and from a fixed effects model was 0.59 (0.39, 0.78) for TMS treatment and 1.55 (1.07, 2.03) for ECT treatment. TMS, across applied stimulation sites and parameters, can exert a significant, albeit modest, positive effect on the motor function of patients with PD. ECT also may exert a significant effect on motor function in PD patients.

Logroscino G. · Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. · Environ Health Perspect. · Pubmed #16140634 links to  free full text

Abstract: Parkinson disease (PD) is of unknown but presumably multifactorial etiology. Neuropathologic studies and animal models show that exposure to environmental neurotoxicants can determine progressive damage in the substantia nigra many years before the onset of clinical parkinsonism. Therefore, PD, like other neurologic diseases related to aging, may be determined by exposures present in the environment early during the life span or even during pregnancy. Recent epidemiologic studies have focused on the possible role of environmental risk factors present during adult life or aging. Smoking and coffee drinking have consistently been identified to have protective associations, whereas roles of other risk factors such as pesticide and infections have been reported in some studies but not replicated in others. Both genetic inheritance and sharing of common environment in the same family explain the increased risk of PD of relatives of PD cases compared with relatives of controls in familial aggregation studies. Much evidence indicates that risk factors that have a long latency or a slow effect could be important for late-onset PD. Further epidemiologic studies are warranted in this area.

Frank S, Kieburtz K, Holloway R, Kim SY. · Boston University, MA, USA. · Neurology. · Pubmed #16033990 No free full text.

Abstract: Placebo, or sham surgery, as a control condition in surgical clinical trials in Parkinson disease (PD) remains controversial. The authors reviewed the adverse effects reported in double blind, placebo surgery controlled trials for PD. Placebo surgeries were generally safe and well tolerated but the number of subjects receiving the procedure was small. Harm occurred more frequently in subjects randomized to the experimental intervention.

Bertram L, Tanzi RE. · Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. · J Clin Invest. · Pubmed #15931380 links to  free full text

Abstract: Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.

Fricchione G, Stefano GB. · Department of Psychiatry, Division of Psychiatry and Medicine, Massachusetts General Hospital, Boston, 02114, USA. · Med Sci Monit. · Pubmed #15874901 No free full text.

Abstract: Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.

Sonntag KC, Simantov R, Isacson O. · Udall Parkinson's Disease Research Center of Excellence, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. · Brain Res Mol Brain Res. · Pubmed #15790528 No free full text.

Abstract: The concept of cell replacement to compensate for cell loss and restore functionality has entered several disease entities including neurodegenerative disorders. Recent clinical studies have shown that transplantation of fetal dopaminergic (DA) cells into the brain of Parkinson's disease (PD) patients can reduce disease-associated motor deficits. However, the use of fetal tissue is associated with practical and ethical problems including low efficiency, variability in the clinical outcome and controversy regarding the use of fetuses as donor. An alternative cell resource could be embryonic stem (ES) cells, which can be cultivated in unlimited amounts and which have the potential to differentiate into mature DA cells. Several differentiation protocols have been developed, and some progress has been made in understanding the mechanisms underlying DA specification in ES cell development, but the "holy grail" in this paradigm, which is the production of sufficient amounts of the "right" therapeutic DA cell, has not yet been accomplished. To achieve this goal, several criteria on the transplanted DA cells need to be fulfilled, mainly addressing cell survival, accurate integration in the brain circuitry, normal function, no tumor formation, and no immunogenicity. Here, we summarize the current state of ES cell-derived DA neurogenesis and discuss the aspects involved in generating an optimal cell source for cell replacement in PD.

Xu K, Bastia E, Schwarzschild M. · MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA. · Pharmacol Ther. · Pubmed #15737407 No free full text.

Abstract: In the pursuit of improved treatments for Parkinson's disease (PD), the adenosine A(2A) receptor has emerged as an attractive nondopaminergic target. Based on the compelling behavioral pharmacology and selective basal ganglia expression of this G-protein-coupled receptor, its antagonists are now crossing the threshold of clinical development as adjunctive symptomatic treatment for relatively advanced PD. The antiparkinsonian potential of A(2A) antagonism has been boosted further by recent preclinical evidence that A(2A) antagonists might favorably alter the course as well as the symptoms of the disease. Convergent epidemiological and laboratory data have suggested that A(2A) blockade may confer neuroprotection against the underlying dopaminergic neuron degeneration. In addition, rodent and nonhuman primate studies have raised the possibility that A(2A) receptor activation contributes to the pathophysiology of dyskinesias-problematic motor complications of standard PD therapy--and that A(2A) antagonism might help prevent them. Realistically, despite being targeted to basal ganglia pathophysiology, A(2A) antagonists may be expected to have other beneficial and adverse effects elsewhere in the central nervous system (e.g., on mood and sleep) and in the periphery (e.g., on immune and inflammatory processes). The thoughtful design of new clinical trials of A(2A) antagonists should take into consideration these counterbalancing hopes and concerns and may do well to shift toward a broader set of disease-modifying as well as symptomatic indications in early PD.

Fischman AJ. · Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA. · Radiol Clin North Am. · Pubmed #15693650 No free full text.

Abstract: FD-PET has proved to be an extremely useful technique for the noninvasive evaluation of nigrostriatal pathophysiology in patients with PD and other movement disorders. The development of ratio methods for image analysis has greatly reduced the complexity of these PET studies and has facilitated data analysis. With the recent advances in cyclotron targetry and automated synthesis modules FD-PET will soon become an important component of the clinical armamentarium.

Snyder H, Wolozin B. · Boston University School of Medicine, 715 ALbany Street, Room L-603, Boston, MA 02118-2526, USA. · J Mol Neurosci. · Pubmed #15655264 No free full text.

Abstract: Parkinson's disease (PD) is a multifactorial disease that appears to arise from the effects of both genetic and environmental influences. Pesticides and heavy metals are the principle environmental factors that appear to impact on PD. The known genetic factors include multiple genes that have been identified in related parkinsonian syndromes, as well as alpha-synuclein. Genes associated with either PD or Parkinson-related disorders include parkin, DJ-1, ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1), nuclear receptor-related factor 1, and alpha-synuclein. Alpha-synuclein is particularly notable because it aggregates readily and is the main component of Lewy bodies (LBs). Aggregated alpha-synuclein binds the proteasome and potently inhibits proteasomal activity. Because ubiquitin accumulates in LBs, and parkin and UCH-L1 also interact with the ubiquitin proteasomal system, proteasomal dysfunction is thought to contribute to the pathophysiology of PD. Increasing numbers of experiments suggest that neurotoxins might interact with alpha-synuclein or other Parkinson-related proteins to contribute to the pathophysiology of PD. Transgenic animal models overexpressing alpha-synuclein develop age-dependent motor dysfunction and inclusions in the brain stem that contain alpha-synuclein. These models are very helpful in elucidating the pathophysiology of PD but do not completely recapitulate the disease process. The relationship between these transgenic models and PD is a subject of intense investigation.

Selkoe DJ. · Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · Nat Cell Biol. · Pubmed #15516999 No free full text.

Abstract: The salutary intersection of fundamental cell biology with the study of disease is well illustrated by the emerging elucidation of neurodegenerative disorders. Novel mechanisms in cell biology have been uncovered through disease-orientated research; for example, the discovery of presenilin as an intramembrane aspartyl protease that processes many diverse proteins within the lipid bilayer. A common theme has arisen in this field: normally-soluble proteins accumulate, misfold and oligomerize, inducing cytotoxic effects that are particularly devastating in the post-mitotic milieu of the neuron.

Lansbury PT. · Harvard Center for Neurodegeneration and Repair and the Department of Neurology, Harvard Medical School, Center for Neurologic Diseases, Brigham and Women's Hospital, 65 Landsdowne St., Cambridge, Massachusetts 02139, USA. · Nat Med. · Pubmed #15298008 No free full text.

Abstract: Despite the increasing prevalence of Alzheimer's disease, Parkinson's disease and less common neurodegenerative diseases-and despite the large amount of primary research that has been carried out into the causes and pathogenic features of these conditions-progress toward effective treatments has been remarkably slow. Why is this, and what can be done to accelerate it? There are a number of obstacles to effective drug discovery for neurodegeneration, but by considering these problems it is possible to identify lessons for the future.

Scherzer CR, Feany MB. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Trends Genet. · Pubmed #15219388 No free full text.

This publication has no abstract.

Walsh DM, Selkoe DJ. · Department of Neurology, Harvard Medical School, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA. · Protein Pept Lett. · Pubmed #15182223 No free full text.

Abstract: Extracellular fibrous amyloid deposits or intracellular inclusion bodies containing abnormal protein fibrils characterize many different neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies, multiple system atrophy, Huntington's disease, and the transmissible 'prion' dementias. There is strong evidence from genetic, transgenic mouse and biochemical studies to support the idea that the accumulation of protein aggregates in the brain plays a seminal role in the pathogenesis of these diseases. How monomeric proteins ultimately convert to highly polymeric deposits is unknown. However, studies employing, synthetic, cell-derived and purified recombinant proteins suggest that amyloid proteins first come together to form soluble low n-oligomers. Further association of these oligomers results in higher molecular weight assemblies including so-called 'protofibrils' and 'ADDLs' and these eventually exceed solubility limits until, finally, they are deposited as amyloid fibrils. With particular reference to AD and PD, we review recent evidence that soluble oligomers are the principal pathogenic species that drive neuronal dysfunction.

Hallett PJ, Standaert DG. · MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA. · Pharmacol Ther. · Pubmed #15163596 No free full text.

Abstract: N-Methyl-d-aspartate (NMDA) glutamate receptors are a class of excitatory amino acid receptors, which have several important functions in the motor circuits of the basal ganglia, and are viewed as important targets for the development of new drugs to prevent or treat Parkinson's disease (PD). NMDA receptors are ligand-gated ion channels composed of multiple subunits, each of which has distinct cellular and regional patterns of expression. They have complex regulatory properties, with both agonist and co-agonist binding sites and regulation by phosphorylation and protein-protein interactions. They are found in all of the structures of the basal ganglia, although the subunit composition in the various structures is different. NMDA receptors present in the striatum are crucial for dopamine-glutamate interactions. The abundance, structure, and function of striatal receptors are altered by the dopamine depletion and further modified by the pharmacological treatments used in PD. In animal models, NMDA receptor antagonists are effective antiparkinsonian agents and can reduce the complications of chronic dopaminergic therapy (wearing off and dyskinesias). Use of these agents in humans has been limited because of the adverse effects associated with nonselective blockade of NMDA receptor function, but the development of more potent and selective pharmaceuticals holds the promise of an important new therapeutic approach for PD.

Rochet JC, Outeiro TF, Conway KA, Ding TT, Volles MJ, Lashuel HA, Bieganski RM, Lindquist SL, Lansbury PT. · Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Cambridge, MA 02139, USA. · J Mol Neurosci. · Pubmed #15126689 No free full text.

Abstract: Parkinson's disease (PD) is a neurologic disorder resulting from the loss of dopaminergic neurons in the brain. Two lines of evidence suggest that the protein alpha-synuclein plays a role in the pathogenesis of PD: Fibrillar alpha-synuclein is a major component of Lewy bodies in diseased neurons, and two mutations in alpha-synuclein are linked to early-onset disease. Accordingly, the fibrillization of alpha-synuclein is proposed to contribute to neurodegeneration in PD. In this report, we provide evidence that oligomeric intermediates of the alpha-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic. Analyses of protofibrillar alpha-synuclein by atomic force microscopy and electron microscopy indicate that the oligomers consist of spheres, chains, and rings. alpha-Synuclein protofibrils permeabilize synthetic vesicles and form pore-like assemblies on the surface of brain-derived vesicles. Dopamine reacts with alpha-synuclein to form a covalent adduct that slows the conversion of protofibrils to fibrils. This finding suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic alpha-synuclein protofibrils, which might explain why these neurons are most vulnerable to degeneration in PD. Finally, we note that aggregation of alpha-synuclein likely occurs via different mechanisms in the cell versus the test tube. For example, the binding of alpha-synuclein to cellular membranes might influence its self-assembly. To address this point, we have developed a yeast model that might enable the selection of random alpha-synuclein mutants with different membrane-binding affinities. These variants might be useful to test whether membrane binding by alpha-synuclein is necessary for neurodegeneration in transgenic animal models of PD.

Chen JF. · Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. · Drug News Perspect. · Pubmed #14702141 No free full text.

Abstract: Long-term L-dopa treatment of Parkinson's disease can lose its effectiveness and cause development of motor complications such as dyskinesia. Furthermore, L-dopa therapy does not address the fundamental pathological process of dopaminergic neurodegeneration in Parkinson's disease. This prompts a search for an alternative or complementary therapy for Parkinson's disease to overcome these limitations. During the last 5 years, the adenosine A(2A) receptor has emerged as an attractive target for Parkinson's disease therapy, primarily because of its localized expression in striatum and motor enhancement function. Recent genetic and pharmacological studies indicate that A(2A) receptor antagonists also offer neuroprotective effects and may possibly modify chronic L-dopa-induced maladaptive responses in animal models of Parkinson's disease. This review summarizes multiple potential benefits of the A(2A) receptor blockade in treating the motor symptoms as well as the underlying dopaminergic neurodegeneration of Parkinson's disease.

Ascherio A, Chen H. · Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. · Neurology. · Pubmed #14663011 No free full text.

This publication has no abstract.

Standaert DG. · Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Neurology. · Pubmed #14663006 No free full text.

This publication has no abstract.

Yarmush ML, Banta S. · Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Shriners Burns Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. · Annu Rev Biomed Eng. · Pubmed #14527316 No free full text.

Abstract: The field of metabolic engineering encompasses a powerful set of tools that can be divided into (a) methods to model complex metabolic pathways and (b) techniques to manipulate these pathways for a desired metabolic outcome. These tools have recently seen increased utility in the medical arena, and this paper aims to review significant accomplishments made using these approaches. The modeling of metabolic pathways has been applied to better understand disease-state physiology in a variety of cellar, subcellular, and organ systems, including the liver, heart, mitochondria, and cancerous cells. Metabolic pathway engineering has been used to generate cells with novel biochemical functions for therapeutic use, and specific examples are provided in the areas of glycosylation engineering and dopamine-replacement therapy. In order to document the potential of applying both metabolic modeling and pathway manipulation, we describe pertinent advances in the field of diabetes research. Undoubtedly, as the field of metabolic engineering matures and is applied to a wider array of problems, new advances and therapeutic strategies will follow.