Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system.
Deniz Kirik,Carl Rosenblad,Corinna Burger,Cecilia Lundberg,Teit E. Johansen,Nicholas Muzyczka,Ronald J. Mandel,Anders Björklund +7 more
TLDR
It is shown that nigral dopamine neurons are selectively vulnerable to high levels of either wild-type or mutant α-synuclein, pointing to a key role for α- Synuclein in the pathogenesis of Parkinson's disease.Abstract:
Recombinant adeno-associated viral vectors display efficient tropism for transduction of the dopamine neurons of the substantia nigra. Taking advantage of this unique property of recombinant adeno-associated viral vectors, we expressed wild-type and A53T mutated human α-synuclein in the nigrostriatal dopamine neurons of adult rats for up to 6 months. Cellular and axonal pathology, including α-synuclein-positive cytoplasmic inclusions and swollen, dystrophic neurites similar to those seen in brains from patients with Parkinson9s disease, developed progressively over time. These pathological alterations occurred preferentially in the nigral dopamine neurons and were not observed in other nondopaminergic neurons transduced by the same vectors. The degenerative changes were accompanied by a loss of 30–80% of the nigral dopamine neurons, a 40–50% reduction of striatal dopamine, and tyrosine hydroxylase levels that was fully developed by 8 weeks. Significant motor impairment developed in those animals in which dopamine neuron cell loss exceeded a critical threshold of 50–60%. At 6 months, signs of cell body and axonal pathology had subsided, suggesting that the surviving neurons had recovered from the initial insult, despite the fact that α-synuclein expression was maintained at a high level. These results show that nigral dopamine neurons are selectively vulnerable to high levels of either wild-type or mutant α-synuclein, pointing to a key role for α-synuclein in the pathogenesis of Parkinson9s disease. Targeted overexpression of α-synuclein in the nigrostriatal system may provide a new animal model of Parkinson9s disease that reproduces some of the cardinal pathological, neurochemical, and behavioral features of the human disease.read more
Citations
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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.
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Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution
TL;DR: The 'new view' of these diseases suggests that other degenerative conditions could have similar underlying origins to those of the amyloidoses, and suggests some intriguing new factors that could be of great significance in the evolution of biological molecules and the mechanisms that regulate their behaviour.
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100 years of Lewy pathology
TL;DR: The relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders is reviewed.
Journal ArticleDOI
α-Synuclein in Parkinson’s Disease
TL;DR: The role of α-synuclein in Parkinson's disease has been investigated in this article, showing that α-Synuclein may contribute to PD pathogenesis in a number of ways, but it is generally thought that its aberrant soluble oligomeric conformations, termed protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death.
Journal ArticleDOI
Intravesicular Localization and Exocytosis of α-Synuclein and its Aggregates
TL;DR: It is shown that a small percentage of newly synthesized α-syn is rapidly secreted from cells via unconventional, endoplasmic reticulum/Golgi-independent exocytosis and this finding proves that intravesicular localization and secretion are part of normal life cycle of α- syn and might also contribute to pathological function of this protein.
References
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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
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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
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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
Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
Hideki Shimura,Nobutaka Hattori,Shin-ichiro Kubo,Yoshikuni Mizuno,Shuichi Asakawa,Shinsei Minoshima,Nobuyoshi Shimizu,Kazuhiro Iwai,Tomoki Chiba,Keiji Tanaka,Toshiaki Suzuki +10 more
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