scholarly journals Pathological ATX3 Expression Induces Cell Perturbations in E. coli as Revealed by Biochemical and Biophysical Investigations

2021 ◽  
Vol 22 (2) ◽  
pp. 943
Author(s):  
Diletta Ami ◽  
Barbara Sciandrone ◽  
Paolo Mereghetti ◽  
Jacopo Falvo ◽  
Tiziano Catelani ◽  
...  
Keyword(s):  
Cell Envelope ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Intact Cells ◽  
E Coli ◽  
Fourier Transform Infrared Microspectroscopy ◽  
Electron Microscopy Analysis ◽  
Microscopy Analysis ◽  
The Fourier Transform ◽  
Type 3

Amyloid aggregation of human ataxin-3 (ATX3) is responsible for spinocerebellar ataxia type 3, which belongs to the class of polyglutamine neurodegenerative disorders. It is widely accepted that the formation of toxic oligomeric species is primarily involved in the onset of the disease. For this reason, to understand the mechanisms underlying toxicity, we expressed both a physiological (ATX3-Q24) and a pathological ATX3 variant (ATX3-Q55) in a simplified cellular model, Escherichia coli. It has been observed that ATX3-Q55 expression induces a higher reduction of the cell growth compared to ATX3-Q24, due to the bacteriostatic effect of the toxic oligomeric species. Furthermore, the Fourier transform infrared microspectroscopy investigation, supported by multivariate analysis, made it possible to monitor protein aggregation and the induced cell perturbations in intact cells. In particular, it has been found that the toxic oligomeric species associated with the expression of ATX3-Q55 are responsible for the main spectral changes, ascribable mainly to the cell envelope modifications. A structural alteration of the membrane detected through electron microscopy analysis in the strain expressing the pathological form supports the spectroscopic results.

Mitochondrial impairment in patients with spinocerebellar ataxia type 3

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
L Schöls ◽  
J Andrich ◽  
H Przuntek ◽  
K Müller ◽  
J Zange
Keyword(s):  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Mitochondrial Impairment ◽  
Type 3

scholarly journals A fine balance between Prpf19 and Exoc7 in achieving degradation of aggregated protein and suppression of cell death in spinocerebellar ataxia type 3

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Zhefan Stephen Chen ◽  
Xiaoying Huang ◽  
Kevin Talbot ◽  
Ho Yin Edwin Chan
Keyword(s):  
Spinocerebellar Ataxia ◽  
E3 Ligase ◽  
Spinocerebellar Ataxia Type ◽  
Disease Genes ◽  
Spinocerebellar Ataxia Type 3 ◽  
E3 Ligases ◽  
Protein Ubiquitination ◽  
Polyq Protein ◽  
Polyq Diseases ◽  
Type 3

AbstractPolyglutamine (polyQ) diseases comprise Huntington’s disease and several subtypes of spinocerebellar ataxia, including spinocerebellar ataxia type 3 (SCA3). The genomic expansion of coding CAG trinucleotide sequence in disease genes leads to the production and accumulation of misfolded polyQ domain-containing disease proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular protein clearance pathways, the activity of the ubiquitin–proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic proteins. Emerging evidence demonstrates that UPS plays a crucial role in the pathogenesis of polyQ diseases. Ubiquitin (Ub) E3 ligases catalyze the transfer of a Ub tag to label proteins destined for proteasomal clearance. In this study, we identified an E3 ligase, pre-mRNA processing factor 19 (Prpf19/prp19), that modulates expanded ataxin-3 (ATXN3-polyQ), disease protein of SCA3, induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Prpf19/prp19 promotes poly-ubiquitination and degradation of mutant ATXN3-polyQ protein. Our data further demonstrated the nuclear localization of Prpf19/prp19 is essential for eliciting its modulatory function towards toxic ATXN3-polyQ protein. Intriguingly, we found that exocyst complex component 7 (Exoc7/exo70), a Prpf19/prp19 interacting partner, modulates expanded ATXN3-polyQ protein levels and toxicity in an opposite manner to Prpf19/prp19. Our data suggest that Exoc7/exo70 exerts its ATXN3-polyQ-modifying effect through regulating the E3 ligase function of Prpf19/prp19. In summary, this study allows us to better define the mechanistic role of Exoc7/exo70-regulated Prpf19/prp19-associated protein ubiquitination pathway in SCA3 pathogenesis.

scholarly journals Polyglutamine‐Expanded Ataxin‐3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood

2021 ◽  
Author(s):  
Jeannette Hübener‐Schmid ◽  
Kirsten Kuhlbrodt ◽  
Julien Peladan ◽  
Jennifer Faber ◽  
Magda M. Santana ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Peripheral Blood ◽  
Spinocerebellar Ataxia Type ◽  
Target Engagement ◽  
Spinocerebellar Ataxia Type 3 ◽  
Type 3

scholarly journals Generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line SCA3.B11

2016 ◽  
Vol 16 (3) ◽  
pp. 589-592 ◽  
Author(s):  
Susanne K. Hansen ◽  
Helena Borland ◽  
Lis F. Hasholt ◽  
Zeynep Tümer ◽  
Jørgen E. Nielsen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Spinocerebellar Ataxia ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Spinocerebellar Ataxia Type ◽  
Stem Cell Line ◽  
Spinocerebellar Ataxia Type 3 ◽  
Induced Pluripotent ◽  
Type 3

scholarly journals Generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line SCA3.A11

2016 ◽  
Vol 16 (3) ◽  
pp. 553-556 ◽  
Author(s):  
Susanne K. Hansen ◽  
Helena Borland ◽  
Lis F. Hasholt ◽  
Zeynep Tümer ◽  
Jørgen E. Nielsen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Line ◽  
Spinocerebellar Ataxia ◽  
Pluripotent Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Spinocerebellar Ataxia Type ◽  
Stem Cell Line ◽  
Spinocerebellar Ataxia Type 3 ◽  
Induced Pluripotent ◽  
Type 3

scholarly journals Recruitment and the Role of Nuclear Localization in Polyglutamine-mediated Aggregation

1998 ◽  
Vol 143 (6) ◽  
pp. 1457-1470 ◽  
Author(s):  
Matthew K. Perez ◽  
Henry L. Paulson ◽  
Sagun J. Pendse ◽  
Sarah J. Saionz ◽  
Nancy M. Bonini ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Green Fluorescence Protein ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 3 ◽  
Eyes Absent ◽  
Disease Protein ◽  
Glutamine Repeat ◽  
Type 3

The inherited neurodegenerative diseases caused by an expanded glutamine repeat share the pathologic feature of intranuclear aggregates or inclusions (NI). Here in cell-based studies of the spinocerebellar ataxia type-3 disease protein, ataxin-3, we address two issues central to aggregation: the role of polyglutamine in recruiting proteins into NI and the role of nuclear localization in promoting aggregation. We demonstrate that full-length ataxin-3 is readily recruited from the cytoplasm into NI seeded either by a pathologic ataxin-3 fragment or by a second unrelated glutamine-repeat disease protein, ataxin-1. Experiments with green fluorescence protein/polyglutamine fusion proteins show that a glutamine repeat is sufficient to recruit an otherwise irrelevant protein into NI, and studies of human disease tissue and a Drosophila transgenic model provide evidence that specific glutamine-repeat–containing proteins, including TATA-binding protein and Eyes Absent protein, are recruited into NI in vivo. Finally, we show that nuclear localization promotes aggregation: an ataxin-3 fragment containing a nonpathologic repeat of 27 glutamines forms inclusions only when targeted to the nucleus. Our findings establish the importance of the polyglutamine domain in mediating recruitment and suggest that pathogenesis may be linked in part to the sequestering of glutamine-containing cellular proteins. In addition, we demonstrate that the nuclear environment may be critical for seeding polyglutamine aggregates.

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