Defects in very long chain fatty acid synthesis enhance alpha-synuclein toxicity in a yeast model of Parkinson's disease.
Defects in very long chain fatty acid synthesis enhance alpha-synuclein toxicity in a yeast model of Parkinson's disease.
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DOI：
10.1371/journal.pone.0015946
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发表时间：
2011-01-11
期刊：
影响因子：
3.7
通讯作者：
Witt SN
中科院分区：
文献类型：
--
作者：
Lee YJ;Wang S;Slone SR;Yacoubian TA;Witt SN
我们鉴定了三个酿酒酵母脂伸长酶缺失突变体(elo1Δ、elo2Δ和elo3Δ)，它们增强了α-突触核蛋白(α-SYN)的毒性。这些延长酶在内质网(ER)中起作用，催化中链脂肪酸延长为极长链脂肪酸，这是鞘磷脂的一种成分。与野生型细胞相比，在不表达α-SYN的情况下，不同的ELO突变体没有表现出生长缺陷，没有活性氧积累，并且衰老细胞的存活率略有下降。随着(WT，A53T或E46K)α-SYN的表达，不同的ELO突变体表现出严重的生长缺陷(尽管A30P对生长的影响可以忽略不计)，ROS积累，异常的蛋白质运输，与野生型细胞相比，老化细胞的存活率显著下降。神经酰胺合成抑制剂Myriocin和FB1对表达(WT、A53T或E46K)α-SYN的野生型酵母细胞具有极强的毒性，但对表达A30P的细胞的毒性要小得多。延长酶突变体和神经酰胺合成抑制剂增强了通过内质网的WTα-SYN、A53T和E46K的毒性，但对不通过内质网的A30P的影响可以忽略不计。内质网神经酰胺-鞘磷脂稳态的破坏显著增强了α-SYN(WT，A53T和E46K)的毒性。
We identified three S. cerevisiae lipid elongase null mutants (elo1Δ, elo2Δ, and elo3Δ) that enhance the toxicity of alpha-synuclein (α-syn). These elongases function in the endoplasmic reticulum (ER) to catalyze the elongation of medium chain fatty acids to very long chain fatty acids, which is a component of sphingolipids. Without α-syn expression, the various elo mutants showed no growth defects, no reactive oxygen species (ROS) accumulation, and a modest decrease in survival of aged cells compared to wild-type cells. With (WT, A53T or E46K) α-syn expression, the various elo mutants exhibited severe growth defects (although A30P had a negligible effect on growth), ROS accumulation, aberrant protein trafficking, and a dramatic decrease in survival of aged cells compared to wild-type cells. Inhibitors of ceramide synthesis, myriocin and FB1, were extremely toxic to wild-type yeast cells expressing (WT, A53T, or E46K) α-syn but much less toxic to cells expressing A30P. The elongase mutants and ceramide synthesis inhibitors enhance the toxicity of WT α-syn, A53T and E46K, which transit through the ER, but have a negligible effect on A30P, which does not transit through the ER. Disruption of ceramide-sphingolipid homeostasis in the ER dramatically enhances the toxicity of α-syn (WT, A53T, and E46K).
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