Acta Neuropathologica

, 122:75 | Cite as

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

  • Matthias Elstner
  • Christopher M. Morris
  • Katharina Heim
  • Andreas Bender
  • Divya Mehta
  • Evelyn Jaros
  • Thomas Klopstock
  • Thomas Meitinger
  • Douglass M. Turnbull
  • Holger Prokisch
Original Paper

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.

Keywords

Parkinson’s disease Aging Dopaminergic neuron Glia Gene expression Pathway analysis Mitochondria Energy metabolism PI3K/Akt mTOR Hif-1α 

Supplementary material

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Matthias Elstner
    • 1
    • 2
  • Christopher M. Morris
    • 3
    • 4
  • Katharina Heim
    • 2
  • Andreas Bender
    • 1
  • Divya Mehta
    • 2
  • Evelyn Jaros
    • 4
  • Thomas Klopstock
    • 1
  • Thomas Meitinger
    • 2
    • 5
  • Douglass M. Turnbull
    • 6
  • Holger Prokisch
    • 2
    • 5
  1. 1.Department of Neurology with Friedrich-Baur-Institute, Klinikum GroßhadernLudwig-Maximilians-UniversityMunichGermany
  2. 2.Institute of Human Genetics, Helmholtz Zentrum MünchenGerman Research Center for Environmental HealthNeuherbergGermany
  3. 3.Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Institute of NeuroscienceNewcastle UniversityNewcastle upon TyneUK
  4. 4.Institute for Ageing and HealthNewcastle UniversityNewcastle upon TyneUK
  5. 5.Institute of Human GeneticsTechnical University MunichMunichGermany
  6. 6.Mitochondrial Research Group, Institute of Ageing and Health, Newcastle University Centre for Brain Ageing and VitalityNewcastle UniversityNewcastle upon TyneUK

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