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Expression analysis of dopaminergic neurons in Parkinson’s disease and aging links transcriptional dysregulation of energy metabolism to cell death

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Abstract

Dopaminergic (DA) neuron degeneration is a feature of brain aging but is markedly increased in patients with Parkinson’s disease (PD). Recent data indicate elevated metabolic stress as a possible explanation for DA neuron vulnerability. Using laser capture microdissection, we isolated DA neurons from the substantia nigra pars compacta of PD patients, age-matched and young controls to determine transcriptional changes by expression profiling and pathway analysis. We verified our findings by comparison to a published dataset. Parallel processing of isolated neurons and bulk tissue allowed the discrimination of neuronal and glial transcription signals. Our data show that genes known to be involved in neural plasticity, axon and synaptic function, as well as cell fate are differentially regulated in aging DA neurons. The transcription patterns in aging suggest a largely maintained expression of genes in energy-related pathways in surviving neurons, possibly supported by the mediation of PPAR/RAR and CREB signaling. In contrast, a profound down-regulation of genes coding for mitochondrial and ubiquitin–proteasome system proteins was seen in PD when compared to the age-matched controls. This is in accordance with the established mitochondrial dysfunction in PD and provides evidence for mitochondrial impairment at the transcriptional level. In addition, the PD neurons had disrupted pathways that comprise a network involved in the control of energy metabolism and cell survival in response to growth factors, oxidative stress, and nutrient deprivation (PI3K/Akt, mTOR, eIF4/p70S6K and Hif-1α). PI3K/Akt and mTOR signaling are central hubs of this network which is of relevance to longevity and—together with induction of mitochondrial biogenesis—may constitute potential targets for therapeutic intervention.

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Acknowledgments

The European Neurological Society funded M.E.; T.K., T.M., and H.P. are members of the German Network for Mitochondrial Disorders (mitoNET, 01GM0862 and 01GM0867); T.M. and H.P. were supported by the Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society (HA-215), the German Federal Ministry of Education and Research (BMBF) funded German National Research Network (NGFNplus #01GS08134) and Systems Biology of Metabotypes (SysMBo #0315494A). CMM gratefully acknowledges funding from the Health Protection Agency UK. Tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases awarded to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and by a grant as part of the Brains for Dementia Research initiative funded by the Alzheimer’s Research Trust and the Alzheimer’s Society.

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Authors and Affiliations

  1. Department of Neurology with Friedrich-Baur-Institute, Klinikum Großhadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany

    Matthias Elstner, Andreas Bender & Thomas Klopstock

  2. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany

    Matthias Elstner, Katharina Heim, Divya Mehta, Thomas Meitinger & Holger Prokisch

  3. Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4AA, UK

    Christopher M. Morris

  4. Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK

    Christopher M. Morris & Evelyn Jaros

  5. Institute of Human Genetics, Technical University Munich, 81675, Munich, Germany

    Thomas Meitinger & Holger Prokisch

  6. Mitochondrial Research Group, Institute of Ageing and Health, Newcastle University Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Douglass M. Turnbull

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  1. Matthias Elstner
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Correspondence to Matthias Elstner.

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Elstner, M., Morris, C.M., Heim, K. et al. Expression analysis of dopaminergic neurons in Parkinson’s disease and aging links transcriptional dysregulation of energy metabolism to cell death. Acta Neuropathol 122, 75–86 (2011). https://doi.org/10.1007/s00401-011-0828-9

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