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Parkinson's Disease and Related Disorders

開催日 2014/9/13
時間 14:00 - 15:00
会場 Poster / Exhibition(Event Hall B)

Exogenous administration of human synthetic α-synuclein fibrils induce Parkinson-like degeneration

  • P3-290
  • Victor Tapias Molina:1,2 Xiaoping Hu:1,2 Kelvin C Luk:3 Virginia M. Lee:3 John T Greenamyre:1,2 
  • 1:Dept Neurol, Univ of Pittsburgh, USA 2:Pittsburgh Institute for Neurodegenerative Diseases 3:Dept of Pathol and Lab Medicine, Univ of Penn, USA 

Intracellular accumulations comprised of α-synuclein (α-syn) amyloid fibrils are hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Missense mutations in the SNCA gene and gene amplifications support a direct causal role for α-syn in PD. Experimental models have shown that overexpression of α-syn resulted in misfolded fibrillar α-syn aggregates (LB and LN) that can be internalized by cells via endocytosis and propagated in a prion-like manner, leading to DA toxicity. Exogenous administration of synthetic α-syn fibrils (PFFs) into primary hippocampal neurons induced intracellular α-syn aggregation. Intrastriatal inoculation of PFFs into mice and non-human primates induced the conversion of endogenous α-syn into pathological LB/LN. The exact mechanism(s) of α-syn toxicity remains elusive. Herein, we investigated the pathogenic effects of administration of human PFFs in cultured rat ventral midbrain DA neurons. The results showed that insoluble α-syn accumulates in the soma of neurons where it forms proteinaceous inclusions comprised of Ser129 phosphorylated α-syn and ubiquitin. Treatment with PFFs enhanced mitochondrial ROS production, protein nitrosylation, and pro-inflammatory mediators expression. Furthermore, alterations in axonal transport-related proteins, changes in mitochondrial dynamic-associated markers, decreased levels of synaptic proteins, DNA damage, caspase-3 activation, and specific DA cell death were observed. Rotenone, a selective inhibitor of the mitochondrial complex I that reproduces several parkinsonian syndrome features in rats, potentiated the above mentioned toxic effects per se. An additive action resulted from the combined exposure to both rotenone and PFFs. Many of the harmful effects found were more prominent in DA cells compared to other type of neurons, suggesting their higher susceptibility to degenerate. These findings provide new insights into the pathogenesis of PD.

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