Journal ArticleDOI
Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies.
Isidro Ferrer,R. Blanco,Margarita Carmona,Berta Puig,M Barrachina,Cristina Gómez,Santiago Ambrosio +6 more
TLDR
Results show that MAPKs are differentially regulated in neurons with α-synuclein-related inclusions and in neuron with abnormal tau deposits in DLB, which suggest a pathogenesis of brain stem and cortical LBs in LB diseases.Abstract:
The expression of mitogen-activated protein kinases, extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinases, c-Jun N-terminal kinases (SAPK/JNK), and p38 kinases is examined in Parkinson disease (PD), in Dementia with Lewy bodies (DLB), covering common and pure forms, and in age-matched controls. The study is geared to gaining understanding about the involvement of these kinases in the pathogenesis of Lewy bodies (LBs) and associated tau deposits in Alzheimer changes in the common form of DLB. Active, phosphorylation dependent MAPK (MAPK-P) is found as granular cytoplasmic inclusions in a subset of cortical neurons bearing abnormal tau deposits in common forms of DLB. Phosphorylated p-38 (p-38-P) decorates neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in common forms of DLB. Phosphorylated SAPK/JNK (SAPK/JNK-P) expression occurs in cortical neurons with neurofibrillary tangles in the common form of DLB. Lewy bodies (LBs) in the brain stem of PD and DLB are stained with anti-ERK-2 antibodies, but they are not recognized by MAPK-P, SAPK/JNK-P and p-38-P. Yet MAPK-P, p-38-P and SAPK/JNK-P immunoreactivity is found in cytoplasmic granules in the vicinity of LBs or in association with irregular-shaped or diffuse alpha-synuclein deposits in a small percentage of neurons, not containing phosphorylated tau, of the brain stem in PD and DLB. MAPK-P, p-38-P and SAPK-P are not expressed in cortical LBs or in cortical neurons with alpha-synuclein-only inclusions in DLB. MAPK-P, p-38-P and SAPK/JNK-P are not expressed in alpha-synuclein-positive neurites (Lewy neurites) in PD and DLB as revealed by double-labeling immunohistochemistry. These results show that MAPKs are differentially regulated in neurons with alpha-synuclein-related inclusions and in neurons with abnormal tau deposits in DLB. Moreover, different kinase expression in brain stem and cortical LBs suggest a pathogenesis of brain stem and cortical LBs in LB diseases. Finally, no relationship has been observed between MAPK-P, p-38-P and SAPK/JNK-P expression and increased nuclear DNA vulnerability, as revealed with the method of in situ end-labeling of nuclear DNA fragmentation, and active, cleaved caspase-3 expression in neurons and glial cells in the substantia nigra in PD and DLB.read more
Citations
More filters
Journal ArticleDOI
p38 MAP-kinases pathway regulation, function and role in human diseases.
Ana Cuenda,Simon Rousseau +1 more
TL;DR: The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases.
Journal ArticleDOI
p38MAPK: stress responses from molecular mechanisms to therapeutics
Lydia R. Coulthard,Danielle E. White,Dominic L. Jones,Michael F. McDermott,Susan A. Burchill +4 more
TL;DR: How this pathway has been exploited for the development of therapeutics and the potential obstacles of targeting this promiscuous protein kinase pathway for the treatment of different diseases are summarized.
Journal ArticleDOI
The Lewy body in Parkinson's disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates.
TL;DR: The histological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates called Lewy bodies (LBs) as discussed by the authors, which is considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs.
Journal ArticleDOI
Cellular pathology of Parkinson's disease: astrocytes, microglia and inflammation.
Peter Teismann,Jörg B. Schulz +1 more
TL;DR: The different aspects of activated glial cells and potential mechanisms that mediate or protect against cell loss in PD are discussed.
Journal ArticleDOI
PINK1 protein in normal human brain and Parkinson's disease
Sonia Gandhi,Miratul M. K. Muqit,Lee Stanyer,Daniel G. Healy,Patrick M. Abou-Sleiman,Iain P. Hargreaves,Simon J.R. Heales,M Ganguly,L Parsons,A J Lees,David S. Latchman,Janice L. Holton,Nicholas W. Wood,Tamas Revesz +13 more
TL;DR: In vivo morphological and biochemical evidence is provided for the first time to support a mitochondrial localization of PINK1 and underpin the significance of mitochondrial dysfunction in the pathogenesis of nigral cell degeneration in Parkinson's disease.
References
More filters
Journal ArticleDOI
Alpha-synuclein in Lewy bodies.
Maria Grazia Spillantini,Marie L. Schmidt,Virginia M.-Y. Lee,John Q. Trojanowski,Ross Jakes,Michel Goedert +5 more
TL;DR: Strong staining of Lewy bodies from idiopathic Parkinson's disease with antibodies for α-synuclein, a presynaptic protein of unknown function which is mutated in some familial cases of the disease, indicates that the LewY bodies from these two diseases may have identical compositions.
Journal ArticleDOI
Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) Report of the consortium on DLB international workshop
Ian G. McKeith,Douglas Galasko,Kenji Kosaka,Elaine K. Perry,Dennis W. Dickson,L. A. Hansen,David P. Salmon,James Lowe,Suzanne S. Mirra,E. J. Byrne,Graham Lennox,Niall Quinn,J.A. Edwardson,Paul G. Ince,Catherine Bergeron,Alistair Burns,Bruce L. Miller,Simon Lovestone,Daniel Collerton,E. N. H. Jansen,Clive Ballard,R. A. I. De Vos,Gordon K. Wilcock,Kurt A. Jellinger,Robert H. Perry +24 more
TL;DR: This work identified progressive disabling mental impairment progressing to dementia as the central feature of DLB, and identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD.
Journal ArticleDOI
α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies
TL;DR: It is shown thatLewy bodies and Lewy neurites from Parkinson’s disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino- terminal and carboxyl-terminal sequences of α-synuclein, showing the presence of full- length or close to full-length α- synuclein.
Journal ArticleDOI
Mitogen-activated protein kinase pathways.
Megan Robinson,Melanie H. Cobb +1 more
TL;DR: Recent advances in the study of mitogen-activated protein kinase cascades include the cloning of genes encoding novel members of the cascades, further definition of the roles of the cascade in responses to extracellular signals, and examination of cross-talk between different cascades.
Journal ArticleDOI
Caspases: killer proteases
TL;DR: Caspases (cysteinyl aspartate-specific proteinases) mediate highly specific proteolytic cleavage events in dying cells, which collectively manifest the apoptotic phenotype.
Related Papers (5)
Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more