Journal ArticleDOI
Expression analysis of dopaminergic neurons in Parkinson's disease and aging links transcriptional dysregulation of energy metabolism to cell death
Matthias Elstner,Matthias Elstner,Christopher Morris,Katharina Heim,Andreas Bender,Divya Mehta,Evelyn Jaros,Thomas Klopstock,Thomas Meitinger,Thomas Meitinger,Douglass M. Turnbull,Holger Prokisch,Holger Prokisch +12 more
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TLDR
In this article, the authors used a laser capture microdissection to isolate dopamine 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.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.read more
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Mechanism and medical implications of mammalian autophagy
Ivan Dikic,Zvulun Elazar +1 more
TL;DR: It is now apparent that autophagy is deregulated in the context of various human pathologies, including cancer and neurodegeneration, and its modulation has considerable potential as a therapeutic approach.
Journal ArticleDOI
The Role of Oxidative Stress in Parkinson’s Disease
TL;DR: Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD, but therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression.
Journal ArticleDOI
The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration.
David Heras-Sandoval,Jazmin M. Pérez-Rojas,Jacqueline Hernández-Damián,José Pedraza-Chaverri +3 more
TL;DR: The interplay between the PI3K/AKT/mTOR pathway and the autophagic process is complex and a more detailed examination of tissue from patients suffering neurodegenerative diseases and of animal and cellular models is needed.
Journal ArticleDOI
Selective neuronal vulnerability in Parkinson disease.
TL;DR: The evidence for and against the spreading LP model are discussed, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.
Journal ArticleDOI
Parkinson disease: from pathology to molecular disease mechanisms
David T. Dexter,Peter Jenner +1 more
TL;DR: Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have expanded knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals.
References
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Staging of brain pathology related to sporadic Parkinson’s disease
TL;DR: This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.
Journal ArticleDOI
Parkinson's disease: Mechanisms and models
TL;DR: PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
Journal ArticleDOI
Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium
Ian G. McKeith,Ian G. McKeith,Dennis W. Dickson,James Lowe,Murat Emre,John T. O'Brien,Howard Feldman,Jeffrey L. Cummings,John E. Duda,Carol F. Lippa,Elaine K. Perry,Dag Aarsland,Hiroyuki Arai,Clive Ballard,B. F. Boeve,David J. Burn,Durval C. Costa,T. Del Ser,Bruno Dubois,Douglas Galasko,Serge Gauthier,Christopher G. Goetz,Estrella Gómez-Tortosa,Glenda M. Halliday,L. A. Hansen,John Hardy,Takeshi Iwatsubo,Raj N. Kalaria,Daniel I. Kaufer,Rose Anne Kenny,Amos D. Korczyn,Kenji Kosaka,Virginia M.-Y. Lee,Andrew J. Lees,Irene Litvan,Elisabet Londos,Oscar L. Lopez,Satoshi Minoshima,Yoshikuni Mizuno,José Antonio Molina,Elizabeta B. Mukaetova-Ladinska,Florence Pasquier,Robert H. Perry,Jörg B. Schulz,John Q. Trojanowski,Masahito Yamada +45 more
TL;DR: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them as mentioned in this paper.
Journal ArticleDOI
Ageing and parkinson's disease: substantia nigra regional selectivity
Julian Fearnley,Andrew J. Lees +1 more
TL;DR: It is suggested that age-related attrition of pigmented nigral cells is not an important factor in the pathogenesis of Parkinson's disease and the regional selectivity of PD is relatively specific.
Journal ArticleDOI
PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
Derek P. Narendra,Seok Min Jin,Atsushi Tanaka,Der-Fen Suen,Clement A. Gautier,Jie Shen,Mark R. Cookson,Richard J. Youle +7 more
TL;DR: The authors suggest that PINK1 and Parkin form a pathway that senses damaged mitochondria and selectively targets them for degradation.