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.; Shelkovnikova, Tatyana A.

doi:10.1186/s13024-015-0014-y

Cited by 29 publications

(52 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Primary cultures of mouse hippocampal neurons were prepared from P1 litters of WT and Neat1 -/mice as described previously (Kukharsky et al, 2015). Neurons were transfected with pEGFP-C1 plasmid using Lipofectamine2000 (Life Technologies) and imaged 24 h post-transfection, using BX61 microscope equipped with F-View II camera and CellF software.…”

Section: Primary Mouse Hippocampal Culturesmentioning

confidence: 99%

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Kukharsky

Ninkina

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

NEAT1 is a highly and ubiquitously expressed long non-coding RNA (lncRNA) which serves as an important regulator of cellular stress response. However, the physiological role of NEAT1 in the central nervous system (CNS) is still poorly understood. In the current study, we addressed this by characterising the CNS function in the Neat1 knockout mouse model (Neat1 -/mice), using a combination of behavioural phenotyping, electrophysiology and expression analysis. RNAscope® in situ hybridisation revealed that in wild-type mice, Neat1 is expressed evenly across the CNS, with high expression in glial cells and low expression in neurons. Loss of Neat1 in mice results in an inadequate reaction to physiological stress manifested as hyperlocomotion and panic escape response. In addition, Neat1 -/mice display deficits in social interaction and rhythmic patterns of activity but retain normal motor function and memory. Neat1 -/mice do not present with neuronal loss, overt neuroinflammation or gross synaptic dysfunction in the brain. However, cultured Neat1 -/neurons are characterised by hyperexcitability and dysregulated calcium homeostasis, and stress-induced neuronal activity is also augmented in Neat1 -/mice in vivo. Gene expression analysis showed that Neat1 may act as a weak positive regulator of multiple genes in the brain. Furthermore, loss of Neat1 affects alternative splicing of genes important for the CNS function and implicated in neurological diseases. Overall, our data suggest that Neat1 is involved in stress signaling in the brain and fine-tunes the CNS functions to enable adaptive behaviour in response to physiological stress.

show abstract

Section: Primary Mouse Hippocampal Culturesmentioning

confidence: 99%

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Kukharsky

Ninkina

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…SS18L1 encodes the calcium-responsive transactivator (CREST) protein which is an essential component of the nBAF neuron-specific chromatin remodeling complex that is related to the yeast SWI/SNF chromatin remodeling complex [49][50][51]. Overexpression of CREST inhibits neurite outgrowth in cultured neurons and causes retina degeneration in transgenic Drosophila [48,52]. Also, CREST co-immunoprecipitates with FUS in neuron lysates [48,52].…”

Section: Introductionmentioning

confidence: 99%

“…In cultured cells, transformed CREST forms predominantly nuclear dots with some cytoplasmic foci. Also, like other ALS associated proteins, CREST is recruited to stressinduced ribonucleoprotein particle (RNP) granules [52,53]. RNP proteins must reversibly aggregate in physiological granules as part of their normal cellular function, but this ability to aggregate could lead to the formation of pathological aggregates.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

Park

Watanabe

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Proteins associated with familial neurodegenerative disease often aggregate in patients' neurons.Several such proteins, e.g. TDP-43, aggregate and are toxic when expressed in yeast. Deletion of the ATXN2 ortholog, PBP1, reduces yeast TDP-43 toxicity, which led to identification of ATXN2 as an amyotrophic lateral sclerosis (ALS) risk factor and therapeutic target. Likewise, new yeast neurodegenerative disease models could facilitate identification of other risk factors and targets.Mutations in SS18L1, encoding the calcium-responsive transactivator (CREST) chromatin-remodeling protein, are associated with ALS. We show that CREST is toxic in yeast and, like the yeast chromatinremodeling factor SWI1, CREST inhibits silencing of FLO genes. Toxicity of CREST is enhanced by the [PIN + ] prion and reduced by deletion of PBP1/ATXN2. CREST forms nuclear and occasionally cytoplasmic foci that stain with an amyloid dye. Overexpression of PBP1 caused considerable CREST co-localization with PBP1 tagged cytoplasmic granules which might promote toxic aggregation of CREST. In accord with the yeast data, we show that the Drosophila ortholog of human ATXN2, dAtx2, is a potent enhancer of CREST toxicity. Down regulation of dAtx2 in flies overexpressing CREST in retinal ganglion cells was sufficient to almost entirely rescue the severe degenerative phenotype induced by human CREST. These results extend the spectrum of ALS associated proteins affected by PBP1/ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases. Author summaryMutations in the calcium-responsive transactivator (CREST) protein have been shown to cause amyotrophic lateral sclerosis (ALS). Here we show that the human CREST protein expressed in yeast forms nuclear aggregates and is toxic. We also show that ATXN2, previously shown to modify ALS toxicity caused by mutations in the TDP-43 encoding gene, also modifies toxicity of CREST expressed in either yeast or flies. These results extend the spectrum of ALS associated proteins affected by ATXN2, suggesting that therapies targeting ATXN2 may be effective for a wide range of neurodegenerative diseases.

show abstract

“…Some other less common gene mutations have also been reported in the last decade. These include mutations in ubiquilin-2 gene (UBQLN2), optineurin (OPTN), angiogenin (ANG), heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and calciumresponsive transactivator (CREST) [64][65][66][67] . Some researchers have found that there is correlation between the site of onset and gene mutation.…”

Section: Genetic and Pathological Overlaps Between Als And Ftdmentioning

confidence: 99%

Clinical and laboratory features of ALS

Xu¹

View full text Add to dashboard Cite

show abstract

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

Cited by 29 publications

References 58 publications

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies

Clinical and laboratory features of ALS

Contact Info

Product

Resources

About