title: A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats.
abstract: Conversion of soluble α-synuclein into insoluble and fibrillar inclusions is a hallmark of Parkinson's disease and other synucleinopathies. Accumulating evidence points towards a relationship between its generation at nerve terminals and structural synaptic pathology. Little is known about the pathogenic impact of α-synuclein conversion and deposition at nigrostriatal dopaminergic synapses in transgenic mice, mainly owing to expression limitations of the α-synuclein construct. Here, we explore whether both the rat as a model and expression of the bacterial artificial chromosome construct consisting of human full-length wild-type α-synuclein could exert dopaminergic neuropathological effects. We found that the human promoter induced a pan-neuronal expression, matching the rodent α-synuclein expression pattern, however, with prominent C-terminally truncated fragments. Ageing promoted conversion of both full-length and C-terminally truncated α-synuclein species into insolube and proteinase K-resistant fibres, with strongest accumulation in the striatum, resembling biochemical changes seen in human Parkinson's disease. Transgenic rats develop early changes in novelty-seeking, avoidance and smell before the progressive motor deficit. Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology.
authors: Department of Neurosciences, University of California, San Diego, Medical Teaching Facility, Room 346, 9500 Gilman Drive, MC 0624, La Jolla, CA 92093, USA. silke.nuber@med.uni-tuebingen.de
authors: Silke
authors: S
authors: Nuber
authors: Florian
authors: F
authors: Harmuth
authors: Zacharias
authors: Z
authors: Kohl
authors: Anthony
authors: A
authors: Adame
authors: Margaritha
authors: M
authors: Trejo
authors: Kai
authors: K
authors: Schönig
authors: Frank
authors: F
authors: Zimmermann
authors: Claudia
authors: C
authors: Bauer
authors: Nicolas
authors: N
authors: Casadei
authors: Christiane
authors: C
authors: Giel
authors: Carsten
authors: C
authors: Calaminus
authors: Bernd J
authors: BJ
authors: Pichler
authors: Poul H
authors: PH
authors: Jensen
authors: Christian P
authors: CP
authors: Müller
authors: Davide
authors: D
authors: Amato
authors: Johannes
authors: J
authors: Kornhuber
authors: Peter
authors: P
authors: Teismann
authors: Hodaka
authors: H
authors: Yamakado
authors: Ryosuke
authors: R
authors: Takahashi
authors: Juergen
authors: J
authors: Winkler
authors: Eliezer
authors: E
authors: Masliah
authors: Olaf
authors: O
authors: Riess
mesh_terms: D000818:Animals; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics* / Q000633:toxicity
chemical_list: D051844:alpha-Synuclein