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篇目详细内容 |
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【篇名】 |
Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy |
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【刊名】 |
Protein & Cell |
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【刊名缩写】 |
Protein Cell
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【ISSN】 |
1674-800X |
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【EISSN】 |
1674-8018 |
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【DOI】 |
10.1007/s13238-011-1014-5 |
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【出版社】 |
Higher Education Press and Springer-Verlag Berlin
Heidelberg |
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【出版年】 |
2011 |
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【卷期】 |
2
卷02期 |
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【页码】 |
141-149
页,共
9
页 |
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【作者】 |
Kazuo Fushimi;
Charles Long;
Neha Jayaram;
Xiaoping Chen;
Liming Li;
Jane Y. Wu;
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【关键词】 |
FUS/TLS; protein aggregation; cytotoxicity |
【摘要】 |
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Mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene have been associated with amyotrophic lateral sclerosis (ALS). FUS-positive neuropathology is reported in a range of neurodegenerative diseases, including ALS and fronto-temporal lobar degeneration with ubiquitin-positive pathology (FTLD-U). To examine protein aggregation and cytotoxicity, we expressed human FUS protein in yeast. Expression of either wild type or ALS-associated R524S or P525L mutant FUS in yeast cells led to formation of aggregates and cytotoxicity, with the two ALS mutants showing increased cytotoxicity. Therefore, yeast cells expressing human FUS protein recapitulate key features of FUS-positive neurodegenerative diseases. Interestingly, a significant fraction of FUS expressing yeast cells stained by propidium iodide were without detectable protein aggregates, suggesting that membrane impairment and cellular damage caused by FUS expression may occur before protein aggregates become microscopically detectable and that aggregate formation might protect cells from FUS-mediated cytotoxicity. The N-terminus of FUS, containing the QGSY and G rich regions, is sufficient for the formation of aggregates but not cytotoxicity. The C-terminal domain, which contains a cluster of mutations, did not show aggregation or cytotoxicity. Similar to TDP-43 when expressed in yeast, FUS protein has the intrinsic property of forming aggregates in the absence of other human proteins. On the other hand, the aggregates formed by FUS are thioflavin T-positive and resistant to 0.5% sarkosyl, unlike TDP-43 when expressed in yeast cells. Furthermore, TDP-43 and FUS display distinct domain requirements in aggregate formation and cytotoxicity. |
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