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

Lookup NU author(s): Dr Matthias Elstner, Dr Christopher Morris, Dr Evelyn Jaros, Emeritus Professor Doug Turnbull


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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

Publication metadata

Author(s): Elstner M, Morris CM, Heim K, Bender A, Mehta D, Jaros E, Klopstock T, Meitinger T, Turnbull DM, Prokisch H

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2011

Volume: 122

Issue: 1

Pages: 75-86

Print publication date: 04/05/2011

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer


DOI: 10.1007/s00401-011-0828-9

PubMed id: 21541762

Notes: Demonstrates the general effects of age on gene expression in isolated substantia nigra neurones and then the specific changes associated with parkinsonism showing that abnormal energy metabolsim may be central to PD.


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Funder referenceFunder name
Alzheimer's Research Trust
European Neurological Society
Health Protection Agency UK
Alzheimer's Society
Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases
01GS08134German Federal Ministry of Education and Research (BMBF)
0315494ASystems Biology of Metabotypes
G0400074UK Medical Research Council
HA-215Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society