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Calcium-responsive transactivator (CREST) protein shares a set of structural and functional traits with other proteins associated with amyotrophic lateral sclerosis

Kukharsky, Michail S., Quintiero, Annamaria, Matsumoto, Taisei, Matsukawa, Koji, An, Haiyan, Hashimoto, Tadafumi, Iwatsubo, Takeshi, Buchman, Vladimir L. ORCID: and Shelkovnikova, Tatyana A. ORCID: 2015. Calcium-responsive transactivator (CREST) protein shares a set of structural and functional traits with other proteins associated with amyotrophic lateral sclerosis. Molecular Neurodegeneration 10 , 20. 10.1186/s13024-015-0014-y

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Background Mutations in calcium-responsive transactivator (CREST) encoding gene have been recently linked to ALS. Similar to several proteins implicated in ALS, CREST contains a prion-like domain and was reported to be a component of paraspeckles. Results We demonstrate that CREST is prone to aggregation and co-aggregates with FUS but not with other two ALS-linked proteins, TDP-43 and TAF15, in cultured cells. Aggregation of CREST affects paraspeckle integrity, probably by trapping other paraspeckle proteins within aggregates. Like several other ALS-associated proteins, CREST is recruited to induced stress granules. Neither of the CREST mutations described in ALS alters its subcellular localization, stress granule recruitment or detergent solubility; however Q388stop mutation results in elevated steady-state levels and more frequent nuclear aggregation of the protein. Both wild-type protein and its mutants negatively affect neurite network complexity of unstimulated cultured neurons when overexpressed, with Q388stop mutation being the most deleterious. When overexpressed in the fly eye, wild-type CREST or its mutants lead to severe retinal degeneration without obvious differences between the variants. Conclusions Our data indicate that CREST and certain other ALS-linked proteins share several features implicated in ALS pathogenesis, namely the ability to aggregate, be recruited to stress granules and alter paraspeckle integrity. A change in CREST levels in neurons which might occur under pathological conditions would have a profound negative effect on neuronal homeostasis. Keywords: Amyotrophic lateral sclerosis (ALS); Calcium-responsive transactivator (CREST); SS18L1; Fused in sarcoma (FUS); TAR DNA‐binding protein 43 (TDP‐43); Protein aggregation; Stress granule; Neurodegeneration; Paraspeckle; Nuclear enriched abundant transcript 1 (NEAT1); Transgenic fly

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > QR Microbiology
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Publisher: BioMed Central
ISSN: 1750-1326
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 25 March 2015
Last Modified: 15 Nov 2022 12:24

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