Parkinson Disease: Maguire-Zeiss KA

Maguire-Zeiss KA. · Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, Washington, DC 20057, United States. · Pharmacol Res. · Pubmed #18840530 No free full text.

Abstract: Parkinson's disease is a progressive age-related neurodegenerative disease with invariant loss of substantia nigra dopamine neurons and striatal projections. This disorder is well known for the associated motoric symptoms including resting tremor and the inability to initiate movement. However, it is now apparent that Parkinson's disease is a multisystem disorder with patients exhibiting symptoms derived from peripheral nervous system and extra-nigral dysfunctions in addition to the prototypical nigrostriatal damage. Although the etiology for sporadic Parkinson's disease is unknown, information gleaned from both familial forms of the disease and animal models places misfolded alpha-synuclein at the forefront. The disease is currently without a cure and most therapies target the motoric symptoms relying on increasing dopamine tone. In this review, the role of alpha-synuclein in disease pathogenesis and as a potential therapeutic target focusing on toxic conformers of this protein is considered. The addition of protofibrillar/oligomer-directed neurotherapeutics to the existing armamentarium may extend the symptom-free stage of Parkinson's disease as well as alleviate pathogenesis.

Maguire-Zeiss KA, Mhyre TR, Federoff HJ. · Department of Neuroscience, Georgetown University, Washington, DC 20007, USA. · Exp Neurol. · Pubmed #18035353 No free full text.

Abstract: PD gene therapy clinical trials have primarily focused on increasing the production of dopamine (DA) through supplemental amino acid decarboxylase (AADC) expression, neurotrophic support for surviving dopaminergic neurons (DAN) or altering brain circuitry to compensate for DA neuron loss. The future of PD gene therapy will depend upon resolving a number of important issues that are discussed in this special issue. Of particular importance is the identification of novel targets that are amenable to early intervention prior to the substantial loss of DAN. However, for the most part the etiopathogenesis of PD is unknown making early intervention a challenge and the development of early biomarker diagnostics imperative.

Maguire-Zeiss KA, Federoff HJ. · Center for Aging and Developmental Biology, University of Rochester, School of Medicine and Dentistry, NY 14642, USA. · Ernst Schering Res Found Workshop. · Pubmed #16315613 No free full text.

Abstract: The convergent pathobiologic model of Parkinson's disease stipulates that disparate insults initiate a disease process that obligately share a common pathway leading to cell death. A combinatorial treatment which targets various steps in this pathway is likely to be the most successful therapeutic strategy. As advances are made in the field of neuroimaging and pharmacogenomics, early detection of sporadic PD will become a reality. Early intervention will likely spare more dopaminergic neurons and extend the quality of life for the patient. Continued advancements in the fields of pharmacology, neurosurgery, and gene therapy will strengthen the armamentarium available for the treatment of PD patients.

Maguire-Zeiss KA, Short DW, Federoff HJ. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. · Brain Res Mol Brain Res. · Pubmed #15790526 No free full text.

Abstract: The etiology of Parkinson's disease (PD) is presently unknown. The unifying hallmark of disease is depletion of dopamine and loss of nigrostriatal dopamine neurons. Familial and sporadic forms of the disease are described. The familial mutations occur within alpha-synuclein and molecules involved in protein degradation and mitochondrial function. Sporadic PD is thought to involve the interplay of genetic and environmental factors. Despite disparate initiating triggers, a convergent pathobiologic model for this common neurodegenerative disease has been proposed. Likely players have emerged that may form the basis for this common pathway model of disease. In this review, we examine the role of three most implicated PD pathogenic conspirators: synuclein, dopamine and oxidative stress.

Maguire-Zeiss KA, Federoff HJ. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. · Ann N Y Acad Sci. · Pubmed #12846984 No free full text.

Abstract: The etiology of Parkinson's disease (PD) has yet to be delineated. Human genetic studies as well as neurotoxicant and transgenic animal models of PD suggest that multiple events trigger the initiation of this progressive age-related neurodegenerative disorder. In addition, we propose that despite disparate disease triggers a convergent pathobiologic pathway exists leading to cell death. The common pathway model posits that both familial and sporadic forms of Parkinson's disease obligately share a common pathophysiological substrate. Herein we discuss the evidence for a common pathway model of Parkinson's disease through a review of synuclein transgenic models and outline an approach for the identification of shared therapeutic targets. We end with a discussion of a potential alternative therapy for Parkinson's disease.