A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats

Silke Nuber, Florian Harmuth, Zacharias Kohl, Anthony Adame, Margaritha Trejo, Kai Schönig, Frank Zimmermann, Claudia Bauer, Nicolas Casadei, Christiane Giel, Carsten Calaminus, Bernd J Pichler, Poul H Jensen, Christian P Müller, Davide Amato, Johannes Kornhuber, Peter Teismann, Hodaka Yamakado, Ryosuke Takahashi, Juergen Winkler & 2 others Eliezer Masliah, Olaf Riess

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)412-32
Number of pages21
JournalBrain
Volume136
Issue number 2
DOIs
Publication statusPublished - Feb 2013

Fingerprint

Synucleins
Transgenic Rats
Phenotype
Parkinson Disease
Pathology
Bacterial Artificial Chromosomes
Endopeptidase K
Dopamine Agents
Smell
Presynaptic Terminals
Synapses
Transgenic Mice
Rodentia

Keywords

  • Animals
  • Chromosomes, Artificial, Bacterial
  • Disease Models, Animal
  • Disease Progression
  • Dopaminergic Neurons
  • Humans
  • Parkinson Disease
  • Phenotype
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • alpha-Synuclein

Cite this

Nuber, S., Harmuth, F., Kohl, Z., Adame, A., Trejo, M., Schönig, K., ... Riess, O. (2013). A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats. Brain, 136( 2), 412-32. https://doi.org/10.1093/brain/aws358

A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats. / Nuber, Silke; Harmuth, Florian; Kohl, Zacharias; Adame, Anthony; Trejo, Margaritha; Schönig, Kai; Zimmermann, Frank; Bauer, Claudia; Casadei, Nicolas; Giel, Christiane; Calaminus, Carsten; Pichler, Bernd J; Jensen, Poul H; Müller, Christian P; Amato, Davide; Kornhuber, Johannes; Teismann, Peter; Yamakado, Hodaka; Takahashi, Ryosuke; Winkler, Juergen; Masliah, Eliezer; Riess, Olaf.

In: Brain, Vol. 136, No. 2, 02.2013, p. 412-32.

Research output: Contribution to journalArticle

Nuber, S, Harmuth, F, Kohl, Z, Adame, A, Trejo, M, Schönig, K, Zimmermann, F, Bauer, C, Casadei, N, Giel, C, Calaminus, C, Pichler, BJ, Jensen, PH, Müller, CP, Amato, D, Kornhuber, J, Teismann, P, Yamakado, H, Takahashi, R, Winkler, J, Masliah, E & Riess, O 2013, 'A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats', Brain, vol. 136, no. 2, pp. 412-32. https://doi.org/10.1093/brain/aws358
Nuber, Silke ; Harmuth, Florian ; Kohl, Zacharias ; Adame, Anthony ; Trejo, Margaritha ; Schönig, Kai ; Zimmermann, Frank ; Bauer, Claudia ; Casadei, Nicolas ; Giel, Christiane ; Calaminus, Carsten ; Pichler, Bernd J ; Jensen, Poul H ; Müller, Christian P ; Amato, Davide ; Kornhuber, Johannes ; Teismann, Peter ; Yamakado, Hodaka ; Takahashi, Ryosuke ; Winkler, Juergen ; Masliah, Eliezer ; Riess, Olaf. / A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats. In: Brain. 2013 ; Vol. 136, No. 2. pp. 412-32.
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AU - Müller, Christian P

AU - Amato, Davide

AU - Kornhuber, Johannes

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AU - Yamakado, Hodaka

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