title: Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death.
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.
authors.affiliation: Department of Neurology with Friedrich-Baur-Institute, Klinikum Großhadern, Ludwig-Maximilians-University, Marchioninistr. 15, 81377 Munich, Germany. melstner@med.uni-muenchen.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Elstner
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Morris
authors.forename: Katharina
authors.initials: K
authors.lastname: Heim
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
authors.forename: Evelyn
authors.initials: E
authors.lastname: Jaros
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D016923:Cell Death / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D047492:Peroxisome Proliferator-Activated Receptors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine