Center of Molecular Physiology of the Brain, Department of Neurology, University Medicine Göttingen, Germany.
Acta Neuropathol. 2012 May;123(5):671-83. doi: 10.1007/s00401-011-0926-8. Epub 2011 Dec 14.
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.
纤维状的 α-突触核蛋白是路易体和路易神经突的主要成分，而路易体和路易神经突是帕金森病（PD）的标志性蛋白沉积。α-突触核蛋白基因的倍增以及点突变会导致家族性 PD。然而，α-突触核蛋白在神经退行性变中的确切作用仍不确定。最近在无脊椎动物中的研究表明，寡聚体形式的 α-突触核蛋白而不是纤维状的 α-突触核蛋白介导神经毒性。为了研究 α-突触核蛋白聚集对神经退行性变进展的影响，我们通过重组腺相关病毒（AAV）载体在大鼠黑质（SN）中表达了具有不同纤维化倾向的变体。蛋白酶 K 抗性 α-突触核蛋白聚集体的形成与黑质多巴胺能（DA）神经元和纹状体纤维的丧失相关。与人类野生型（WT）或遗传的 A30P 突变相比，两种前纤维状、基于结构设计的 α-突触核蛋白突变体（即 A56P 和 A30P/A56P/A76P）在黑质 DA 神经元中的聚集体形成较少。然而，只有能够形成纤维的 α-突触核蛋白变体（WT/A30P），而不是寡聚体 α-突触核蛋白物种，诱导成年黑质 DA 神经元持续进行性丧失。这些结果表明，在体内的无脊椎动物和哺乳动物 DA 神经元中存在不同的 α-突触核蛋白神经毒性模式，并表明 α-突触核蛋白的纤维化促进了 PD 患者中发现的黑质 DA 神经元的进行性退化。
