Journal ArticleDOI
Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders
Eliezer Masliah,Edward Rockenstein,Isaac Veinbergs,Margaret Mallory,Makoto Hashimoto,Ayako Takeda,Yutaka Sagara,Abbyann Sisk,Lennart Mucke +8 more
TLDR
Results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.Abstract:
To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.read more
Citations
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α-Synuclein Interacts with Phospholipase D Isozymes and Inhibits Pervanadate-induced Phospholipase D Activation in Human Embryonic Kidney-293 Cells
Bong-Hyun Ahn,Hyangshuk Rhim,Shi Yeon Kim,Young Mo Sung,Mun-Yong Lee,Ju-Youn Choi,Benjamin Wolozin,Jong-Soo Chang,Young Han Lee,Taeg Kyu Kwon,Kwang Chul Chung,Shin-Hee Yoon,Sang June Hahn,Myung-Suk Kim,Yang-Hyeok Jo,Do Sik Min +15 more
TL;DR: Co-transfection studies indicate that the association of α-synuclein with PLD, and modulation of PLD activity, is biologically important, but PLD does not appear to play an essential role in the pathophysiology ofα- synuclein.
Journal ArticleDOI
A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and A beta peptides
TL;DR: This work shows that, in transgenic mice, alpha-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Abeta, and suggests that intracellular alpha- synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.
Journal ArticleDOI
alpha-Synucleinopathy models and human neuropathology: similarities and differences.
TL;DR: The role and thus therapeutic potential of post-translational modifications (ubiquitinylation, oxidation, phosphorylation, truncation) and modifier genes on αSYN neuropathology can now be assessed in valid transgenic mouse models of α-synucleinopathies.
Journal ArticleDOI
A53T-Alpha-Synuclein Overexpression Impairs Dopamine Signaling and Striatal Synaptic Plasticity in Old Mice
Alexander Kurz,Kay L. Double,Isabel Lastres-Becker,Alessandro Tozzi,Michela Tantucci,Vanessa Bockhart,Michael Bonin,Moisés García-Arencibia,Silke Nuber,Falk Schlaudraff,Birgit Liss,Javier Fernández-Ruiz,Manfred Gerlach,Ullrich Wüllner,Hartmut Lüddens,Paolo Calabresi,Georg Auburger,Suzana Gispert +17 more
TL;DR: The dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration, and may help to develop neuroprotective therapeutic approaches.
References
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Journal ArticleDOI
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
TL;DR: A mutation was identified in the α-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype.
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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
Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.
Rejko Krüger,Wilfried Kuhn,Thomas Müller,Dirk Woitalla,Manuel B. Graeber,Sigfried Kösel,Horst Przuntek,Jörg T. Epplen,Ludger Schöls,Olaf Riess +9 more
Journal ArticleDOI
Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.
Dora Games,David S. Adams,Ree Alessandrini,Robin Barbour,Patricia Borthelette,Catherine Blackwell,Tony Carr,J. C. Clemens,Thomas Donaldson,Frances Gillespie,Terry Guido,Stephanie Hagopian,Kelly Johnson-Wood,Karen Khan,Michael K. Lee,Paul Leibowitz,Ivan Lieberburg,Sheila P. Little,Eliezer Masliah,Lisa McConlogue,Martin Montoya-Zavala,Lennart Mucke,Lisa Paganini,Elizabeth Penniman,Michael Power,Dale Schenk,Peter Seubert,Ben W. Snyder,Ferdie Soriano,Hua Tan,James Vitale,Sam Wadsworth,Ben Wolozin,Jun Zhao +33 more
TL;DR: Transgenic mice that express high levels of human mutant APP support a primary role for APP/Aβ in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.
Journal ArticleDOI
Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the hd mutation
Stephen W. Davies,Mark Turmaine,Barbara A. Cozens,Marian DiFiglia,Alan H. Sharp,Christopher A. Ross,Eberhard Scherzinger,Erich E. Wanker,Laura Mangiarini,Gillian P. Bates +9 more
TL;DR: In this paper, the authors observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to 157 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype.
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