title: Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons.
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.
authors.affiliation: Center of Molecular Physiology of the Brain, Department of Neurology, University Medicine Göttingen, Germany. gtasche@gwdg.de
authors.forename: Grit
authors.initials: G
authors.lastname: Taschenberger
authors.forename: Manuel
authors.initials: M
authors.lastname: Garrido
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Tereshchenko
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000473:pathology*; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000494:pharmacology; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D051844:alpha-Synuclein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D011494:Protein Kinases