scholarly journals Stabilization and Degradation Mechanisms of Cytoplasmic Ataxin-1

2015 ◽  
Vol 9s2 ◽  
pp. JEN.S25469
Author(s):  
Mayumi F. Kohiyama ◽  
Sarita Lagalwar
Keyword(s):  
Neurodegenerative Disease ◽  
Nuclear Translocation ◽  
Cellular Protein ◽  
Protein Stabilization ◽  
Spinocerebellar Ataxia Type ◽  
Mutant Form ◽  
Degradation Mechanisms ◽  
Polyglutamine Expansion ◽  
Cerebellar Purkinje Neurons

Aggregation-prone proteins in neurodegenerative disease disrupt cellular protein stabilization and degradation pathways. The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by a coding polyglutamine expansion in the Ataxin-1 gene ( ATXN1), which gives rise to the aggregation-prone mutant form of ATXN1 protein. Cerebellar Purkinje neurons, preferentially vulnerable in SCA1, produce ATXN1 protein in both cytoplasmic and nuclear compartments. Cytoplasmic stabilization of ATXN1 by phosphorylation and 14-3-3-mediated mechanisms ultimately drive translocation of the protein to the nucleus where aggregation may occur. However, experimental inhibition of phosphorylation and 14-3-3 binding results in rapid degradation of ATXN1, thus preventing nuclear translocation and cellular toxicity. The exact mechanism of cytoplasmic ATXN1 degradation is currently unknown; further investigation of degradation may provide future therapeutic targets. This review examines the present understanding of cytoplasmic ATXN1 stabilization and potential degradation mechanisms during normal and pathogenic states.

scholarly journals Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in spinocerebellar ataxia type 1

2020 ◽  
Vol 29 (19) ◽  
pp. 3249-3265
Author(s):  
Ravi Chopra ◽  
David D Bushart ◽  
John P Cooper ◽  
Dhananjay Yellajoshyula ◽  
Logan M Morrison ◽  
...  
Keyword(s):  
Ion Channel ◽  
Spinocerebellar Ataxia ◽  
Selective Vulnerability ◽  
Purkinje Neuron ◽  
Purkinje Neurons ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Gene Dysregulation ◽  
Cerebellar Purkinje Neurons

Abstract Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

scholarly journals Ubiquilin-2 differentially regulates polyglutamine disease proteins

2020 ◽  
Vol 29 (15) ◽  
pp. 2596-2610
Author(s):  
Julia E Gerson ◽  
Nathaniel Safren ◽  
Svetlana Fischer ◽  
Ronak Patel ◽  
Emily V Crowley ◽  
...  
Keyword(s):  
Mouse Models ◽  
Nuclear Translocation ◽  
Full Length ◽  
Spinocerebellar Ataxia Type ◽  
Polyglutamine Disease ◽  
Spinocerebellar Ataxia Type 3 ◽  
Polyglutamine Expansion ◽  
Cellular Models ◽  
Exon 1 ◽  
Nuclear Mutant

Abstract Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins. Here we employ cellular models, primary neurons and mouse models to investigate the potential differential regulation by UBQLN2 of two polyglutamine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3). In cells, overexpressed UBQLN2 selectively lowered levels of full-length pathogenic HTT but not of HTT exon 1 fragment or full-length ATXN3. Consistent with these results, UBQLN2 specifically reduced accumulation of aggregated mutant HTT but not mutant ATXN3 in mouse models of Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3), respectively. Normally a cytoplasmic protein, UBQLN2 translocated to the nuclei of neurons in HD mice but not in SCA3 mice. Remarkably, instead of reducing the accumulation of nuclear mutant ATXN3, UBQLN2 induced an accumulation of cytoplasmic ATXN3 aggregates in neurons of SCA3 mice. Together these results reveal a selective action of UBQLN2 toward polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient to promote UBQLN2-mediated clearance of this class of disease proteins. Additional factors, including nuclear translocation of UBQLN2, may facilitate its action to clear intranuclear, aggregated disease proteins like HTT.

scholarly journals Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1

2020 ◽  
Author(s):  
Ravi Chopra ◽  
David D Bushart ◽  
John P Cooper ◽  
Dhananjay Yellajoshyula ◽  
Logan M Morrison ◽  
...  
Keyword(s):  
Ion Channel ◽  
Spinocerebellar Ataxia ◽  
Selective Vulnerability ◽  
Purkinje Neuron ◽  
Purkinje Neurons ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Gene Dysregulation ◽  
Cerebellar Purkinje Neurons

AbstractSelective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 corepressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.

scholarly journals Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signalled to DNA damage by Ataxia Telangiectasia Mutated kinase

2019 ◽  
Author(s):  
Celeste E. Suart ◽  
Alma M. Perez ◽  
Ismael Al-Ramahi ◽  
Tamara Maiuri ◽  
Juan Botas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Spinocerebellar Ataxia ◽  
Ataxia Telangiectasia ◽  
Neurodegenerative Disorder ◽  
Age At Onset ◽  
Spinocerebellar Ataxia Type ◽  
Ataxia Telangiectasia Mutated ◽  
Spinocerebellar Ataxia Type 1 ◽  
Polyglutamine Expansion

ABSTRACTSpinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington’s Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.

scholarly journals Non-ATG–initiated translation directed by microsatellite expansions

2010 ◽  
Vol 108 (1) ◽  
pp. 260-265 ◽  
Author(s):  
Tao Zu ◽  
Brian Gibbens ◽  
Noelle S. Doty ◽  
Mário Gomes-Pereira ◽  
Aline Huguet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Start Codon ◽  
Spinocerebellar Ataxia Type ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Polyglutamine Expansion ◽  
Transfected Cells ◽  
Cag Expansion ◽  
Ran Translation

Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.

scholarly journals The Protein Tyrosine Kinase p56lck Is Required for Triggering NF-κB Activation upon Interaction of Human Immunodeficiency Virus Type 1 Envelope Glycoprotein gp120 with Cell Surface CD4

1998 ◽  
Vol 72 (7) ◽  
pp. 6207-6214 ◽  
Author(s):  
Laurence Briant ◽  
Véronique Robert-Hebmann ◽  
Claire Acquaviva ◽  
Annegret Pelchen-Matthews ◽  
Mark Marsh ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nuclear Translocation ◽  
Mutant Form ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
In Cells

ABSTRACT We have previously shown that NF-κB nuclear translocation can be observed upon human immunodeficiency virus type 1 (HIV-1) binding to cells expressing the wild-type CD4 molecule, but not in cells expressing a truncated form of CD4 that lacks the cytoplasmic domain (M. Benkirane, K.-T. Jeang, and C. Devaux, EMBO J. 13:5559–5569, 1994). This result indicated that the signaling cascade which controls HIV-1-induced NF-κB activation requires the integrity of the CD4 cytoplasmic tail and suggested the involvement of a second protein that binds to this portion of the molecule. Here we investigate the putative role of p56 lck as a possible cellular intermediate in this signal transduction pathway. Using human cervical carcinoma HeLa cells stably expressing CD4, p56 lck , or both molecules, we provide direct evidence that expression of CD4 and p56 lck is required for HIV-1-induced NF-κB translocation. Moreover, the fact that HIV-1 stimulation did not induce nuclear translocation of NF-κB in cells expressing a mutant form of CD4 at position 420 (C420A) and the wild-type p56 lck indicates the requirement for a functional CD4-p56 lck complex.

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