Abstract
BackgroundMutations 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0014-y) contains supplementary material, which is available to authorized users.
Highlights
Mutations in calcium-responsive transactivator (CREST) encoding gene have been recently linked to Amyotrophic lateral sclerosis (ALS)
To establish if nuclear dot-like structures formed by CREST were related to known nuclear bodies, transfected cells were co-stained for various nuclear body markers
In SH-SY5Y cells with a diffuse/fine-granular nucleoplasmic distribution of CREST-GFP the protein was excluded from nucleolar region identified by ethidium bromide staining, was not enriched in SMN-positive Gems, coilin p80positive Cajal bodies or PML bodies but we detected its enrichment around MALAT1-positive nuclear speckles (Figure 1B)
Summary
Mutations in calcium-responsive transactivator (CREST) encoding gene have been recently linked to ALS. Using exome sequencing in sporadic ALS trios Chesi and co-workers [4] have identified two mutations in the SS18L1 gene which encodes calcium-responsive transactivator (CREST) protein. In the original study CREST was shown to bind chromatin remodeling proteins BAF250 and BRG-1 [6]. It was demonstrated that CREST and a highly homologous protein, SS18, are dedicated subunits of chromatin remodeling complex Brg/Brm-associated factor (BAF), which is an important modulator of transcription of specific gene sets at various stages of neural development [9]. Mutations in components of the BAF complex have been identified in autism, schizophrenia and other neurodevelopmental disorders, arguing that its function is crucial for normal development of the nervous system [10,11]
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