Original Paper

Acta Neuropathologica

, Volume 122, Issue 1, pp 75-86

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

  • Matthias ElstnerAffiliated withDepartment of Neurology with Friedrich-Baur-Institute, Klinikum Großhadern, Ludwig-Maximilians-UniversityInstitute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health Email author 
  • , Christopher M. MorrisAffiliated withMedical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Institute of Neuroscience, Newcastle UniversityInstitute for Ageing and Health, Newcastle University
  • , Katharina HeimAffiliated withInstitute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health
  • , Andreas BenderAffiliated withDepartment of Neurology with Friedrich-Baur-Institute, Klinikum Großhadern, Ludwig-Maximilians-University
  • , Divya MehtaAffiliated withInstitute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health
  • , Evelyn JarosAffiliated withInstitute for Ageing and Health, Newcastle University
  • , Thomas KlopstockAffiliated withDepartment of Neurology with Friedrich-Baur-Institute, Klinikum Großhadern, Ludwig-Maximilians-University
  • , Thomas MeitingerAffiliated withInstitute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Human Genetics, Technical University Munich
  • , Douglass M. TurnbullAffiliated withMitochondrial Research Group, Institute of Ageing and Health, Newcastle University Centre for Brain Ageing and Vitality, Newcastle University
    • , Holger ProkischAffiliated withInstitute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental HealthInstitute of Human Genetics, Technical University Munich

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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.

Keywords

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