Parkinson Disease: Totterdell S

Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ. · Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA. · Parkinsonism Relat Disord. · Pubmed #18585085 links to  free full text

Abstract: Formidable challenges for Parkinson's disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are formed and inflammation is chronic. Nevertheless, isradipine, an L-type calcium-channel blocker, attenuates the degeneration. These data support the validity of the MPTP/p model for unravelling the degenerative processes in PD and testing therapies that slow their progress.

Meredith GE, Halliday GM, Totterdell S. · Department of Cellular and Molecular Pharmacology, Chicago Medical School, Finch University of Health Sciences, 3333 Green Bay Road, North Chicago, IL 60054, USA. · Parkinsonism Relat Disord. · Pubmed #15120093 No free full text.

Abstract: The pace of development of new animal models of Parkinson's disease (PD) has increased dramatically in the recent past, primarily because of the identification of the protein, alpha-synuclein, in Lewy bodies in both idiopathic and familial PD. This discovery has allowed the production of transgenic models that incorporate a form of human, mutant alpha-synuclein from rare familial cases, and has enabled the search for Lewy-body-like aggregations of this protein in toxin-induced models. Indeed, alpha-synuclein-positive inclusions, some of which bear strong resemblance to Lewy bodies, have now been recognized and their formation investigated in several different, environmentally-induced and transgenic models. Nevertheless, these data have yet to provide a uniform theory of inclusion pathogenesis for PD. The aim of this review is not only to summarize the findings to date on alpha-synuclein-immunopositive inclusion bodies, including some new information on Lewy bodies, but also provide a concise viewpoint on their origin and formation in animal models. We will provide evidence for a predicted series of intracellular events that underlie inclusion formation. Triggered by oxidative and metabolic stress, chronic, toxin-treated animals, rather than transgenic models transfected with human alpha-synuclein, eventually produce inclusion bodies that most closely resemble early stages of Lewy bodies. Elucidating the common mechanisms in animal models is a first step towards understanding the role of Lewy bodies and their formation in Parkinson's disease.

Totterdell S, Meredith GE. · Department of Pharmacology, Oxford University, Mansfield Road, Oxford OX1 3QT, UK. · Neuroscience. · Pubmed #16112475 No free full text.

Abstract: Alpha-synuclein is a synaptic associated protein that is found throughout the brain. Although its function is not fully understood, various roles have been proposed, including the mobilization of synaptic vesicles and plasticity. However, interest in this molecule is mainly focused on its role in neurodegenerative diseases such as Parkinson's disease, where it is a major component in cellular inclusions. Although it is widely accepted that alpha-synuclein is distributed to terminals and fibers throughout the brain, the identity of the pathways that contain this protein is not known. To address this issue, we combined immunocytochemistry with anterograde tract-tracing in mouse to identify the projections that are alpha-synuclein immunopositive. We find that it is present in corticostriatal, nigrostriatal and striatonigral terminals. Our data support the concept that alpha-synuclein is normally present in at least some of the terminals of inclusion-forming neurons, but that it is also present in the axonal boutons of neurons that do not apparently accumulate this protein pathologically.

Meredith GE, Totterdell S, Petroske E, Santa Cruz K, Callison RC, Lau YS. · Department of Cellular and Molecular Pharmacology, Chicago Medical School, Finch University of Health Sciences, 3333 Green Bay Road, North Chicago, IL 60064, USA. · Brain Res. · Pubmed #12426058 No free full text.

Abstract: We have detected granular and filamentous inclusions that are alpha-synuclein- and ubiquitin-immunoreactive in the cytoplasm of dopaminergic and cortical neurons of C57/black mice treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid. The immunoreactive aggregates only become evident several weeks after large-scale dopaminergic cell death and a downregulation of alpha-synuclein gene expression. Numerous lipofuscin granules accumulate alpha-synuclein in the nigral and limbic cortical neurons of treated mice. These data provide evidence that insoluble proteins, such as alpha-synuclein, build up as granular and filamentous inclusions in dopaminergic neurons that survive the initial toxic MPTP insult. They further suggest that defective protein degradation rather than altered gene expression underlies deposition of alpha-synuclein and that abundant lysosomal compartments are present to seal off the potentially toxic material.