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  Aggregation of alpha Synuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons.

Taschenberger, G., Garrido, M., Tereshchenko, Y., Baehr, M., Zweckstetter, M., & Kuegler, S. (2012). Aggregation of alpha Synuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons. Acta Neuropathologica, 123(5), 671-683. doi:10.1007/s00401-011-0926-8.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000F-8543-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CAEF-2
Genre: Journal Article

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Taschenberger, G., Author
Garrido, M., Author
Tereshchenko, Y., Author
Baehr, M., Author
Zweckstetter, M.1, Author              
Kuegler, S., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: Fibrillar αSynuclein is the major constituent of Lewy bodies and Lewy neurites, the protein deposits characteristic for Parkinson’s disease (PD). Multiplications of the αSynuclein gene, as well as point mutations cause familial PD. However, the exact role of αSynuclein in neurodegeneration remains uncertain. Recent research in invertebrates has suggested that oligomeric rather than fibrillizing αSynuclein mediates neurotoxicity. To investigate the impact of αSynuclein aggregation on the progression of neurodegeneration, we expressed variants with different fibrillation propensities in the rat substantia nigra (SN) by means of recombinant adeno-associated viral (AAV) vectors. The formation of proteinase K-resistant αSynuclein aggregates was correlated to the loss of nigral dopaminergic (DA) neurons and striatal fibers. Expression of two prefibrillar, structure-based design mutants of αSynuclein (i.e., A56P and A30P/A56P/A76P) resulted in less aggregate formation in nigral DA neurons as compared to human wild-type (WT) or the inherited A30P mutation. However, only the αSynuclein variants capable of forming fibrils (WT/A30P), but not the oligomeric αSynuclein species induced a sustained progressive loss of adult nigral DA neurons. These results demonstrate that divergent modes of αSynuclein neurotoxicity exist in invertebrate and mammalian DA neurons in vivo and suggest that fibrillation of αSynuclein promotes the progressive degeneration of nigral DA neurons as found in PD patients.

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Language(s): eng - English
 Dates: 2011-12-142012-05
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s00401-011-0926-8
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Title: Acta Neuropathologica
  Other : Acta Neuropathol.
Source Genre: Journal
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Publ. Info: Berlin : Springer Verlag
Pages: - Volume / Issue: 123 (5) Sequence Number: - Start / End Page: 671 - 683 Identifier: ISSN: 0001-6322
CoNE: /journals/resource/954925374814_1