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

Autor: Tatyana A. Shelkovnikova, Haiyan An, Takeshi Iwatsubo, Annamaria Quintiero, Koji Matsukawa, Michail S. Kukharsky, Tadafumi Hashimoto, Vladimir L. Buchman, Taisei Matsumoto
Rok vydání: 2015
Předmět:
Zdroj: Molecular Neurodegeneration
ISSN: 1750-1326
DOI: 10.1186/s13024-015-0014-y
Popis: 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
Databáze: OpenAIRE
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