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Title of Journal: Acta Neuropathol

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Abbravation: Acta Neuropathologica

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Springer-Verlag

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DOI

10.1002/chin.200635142

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1432-0533

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Expression analysis of dopaminergic neurons in Par

Authors: Matthias Elstner Christopher M Morris Katharina Heim Andreas Bender Divya Mehta Evelyn Jaros Thomas Klopstock Thomas Meitinger Douglass M Turnbull Holger Prokisch
Publish Date: 2011/05/04
Volume: 122, Issue: 1, Pages: 75-
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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 agematched 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 energyrelated pathways in surviving neurons possibly supported by the mediation of PPAR/RAR and CREB signaling In contrast a profound downregulation of genes coding for mitochondrial and ubiquitin–proteasome system proteins was seen in PD when compared to the agematched 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 Hif1α 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 interventionThe European Neurological Society funded ME TK TM and HP are members of the German Network for Mitochondrial Disorders mitoNET 01GM0862 and 01GM0867 TM and HP 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 HA215 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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