Crowded organelles, lipid accumulation, and abnormal membrane tubulation in cellular models of enhanced α-synuclein membrane interaction.
Crowded organelles, lipid accumulation, and abnormal membrane tubulation in cellular models of enhanced α-synuclein membrane interaction.
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DOI：
10.1016/j.brainres.2021.147349
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发表时间：
2021-05-01
期刊：
影响因子：
2.9
通讯作者：
Dettmer U
中科院分区：
文献类型：
--
作者：
Ericsson M;von Saucken V;Newman AJ;Doehr L;Hoesch C;Kim TE;Dettmer U
我们小组之前的工作表明，α-突触核蛋白（αS） KTKEGV重复基序的某些工程错义突变会破坏蛋白质形成天然多聚体的能力。由此产生的过量单体积聚在富含脂膜的包涵体中，其神经毒性超过了天然家族性PD突变体（如E46K）。我们对富含脂质的包裹体进行了初步表征，发现它们与面包酵母中表达αS时形成的富含αS和囊泡的包裹体相似。我们还谨慎地讨论了富膜包涵体作为丝状路易体前体的可能作用，丝状路易体是帕金森病和其他突触核蛋白病的广泛接受的标志性病理。同时，路易小体显微表征的进展表明，除了αS积聚外，路易小体还存在拥挤的细胞器和脂质膜。这促使我们重新审视神经母细胞瘤细胞中由重复基序变异引起的αS内含物。除了我们之前的表征外，我们发现这些内含物通常可以通过明场显微镜看到，在免疫荧光实验中与内源性囊泡标记物重叠，脂质染料染色阳性，并且可以发现与线粒体密切相关。我们还观察到细胞膜的异常管状，这在诱导系中很微妙，而在瞬间表达大量高度破坏性KTKEGV基序突变体“KLKEGV”的细胞中很明显。以前曾报道过还原系统中的膜管化是αS活性。我们的细胞内实验表明，这种机制可能是细胞中αS异常行为的一个相关方面。
Previous work from our group showed that certain engineered missense mutations to the α-synuclein (αS) KTKEGV repeat motifs abrogate the protein’s ability to form native multimers. The resultant excess monomers accumulate in lipid membrane-rich inclusions associated with neurotoxicity exceeding that of natural familial PD mutants such as E46K. We presented an initial characterization of the lipid-rich inclusions and found similarities to the αS- and vesicle-rich inclusions that form in baker’s yeast when αS is expressed. We also discussed, with some caution, a possible role of membrane-rich inclusions as precursors to filamentous Lewy bodies, the widely accepted hallmark pathology of Parkinson’s disease and other synucleinopathies. In the meantime, advances in the microscopic characterization of Lewy bodies have highlighted the presence of crowded organelles and lipid membranes in addition to αS accumulation. This prompted us to revisit the αS inclusions caused by our repeat motif variants in neuroblastoma cells. In addition to our previous characterization, we found that these inclusions can often be seen by brightfield microscopy, overlap with endogenous vesicle markers in immunofluorescence experiments, stain positive for lipid dyes and can be found to be closely associated with mitochondria. We also observed abnormal tubulation of membranes, which was subtle in inducible lines and pronounced in cells that transiently expressed high amounts of the highly disruptive KTKEGV motif mutant “KLKEGV”. Membrane tubulation had been reported before as an αS activity in reductionist systems. Our in-cellulo demonstration now suggests that this mechanism could possibly be a relevant aspect of aberrant αS behavior in cells.
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影响因子：
16.6
作者：
Fusco, Giuliana;Pape, Tillmann;Stephens, Amberley D.;Mahou, Pierre;Costa, Ana Rita;Kaminski, Clemens F.;Schierle, Gabriele S. Kaminski;Vendruscolo, Michele;Veglia, Gianluigi;Dobson, Christopher M.;De Simone, Alfonso
通讯作者：
De Simone, Alfonso
影响因子：
4.3
作者：
Dettmer U
通讯作者：
Dettmer U
影响因子：
5.3
作者：
Burre, Jacqueline;Sharma, Manu;Suedhof, Thomas C.
通讯作者：
Suedhof, Thomas C.
DOI：
10.1016/0169-328x(91)90043-w
发表时间：
1991-10-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
MAROTEAUX, L;SCHELLER, RH
通讯作者：
SCHELLER, RH
影响因子：
12.7
作者：
FORNO, LS;NORVILLE, RL
通讯作者：
NORVILLE, RL