Intercellular Propagation and Aggregate Seeding of Mutant Ataxin-1

Abstract Intercellular propagation of aggregated protein inclusions along actin-based tunneling nanotubes (TNTs) has been reported as a means of pathogenic spread in Alzheimer’s, Parkinson’s and Huntington’s Disease. Propagation of oligomeric-structured polyglutamine-expanded ataxin-1 (Atxn1[154Q]) has been reported in the cerebellum of a Spinocerebellar ataxia type 1 (SCA1) knock-in mouse to correlate with disease propagation. In this study, we investigated whether a physiologically-relevant polyglutamine-expanded ATXN1 protein (ATXN1[82Q]) could propagate intercellularly. Using a cerebellar-derived live cell model, we observed ATXN1 aggregates form in the nucleus, export out of the nucleus into the cytoplasm, and finally, propagate to neighboring cells along actin-based intercellular connections. Additionally, we observed the facilitation of aggregate-resistant proteins into aggregates given the presence of aggregation-prone proteins within a cell. Taken together, our results support a pathogenic role of intercellular propagation of polyglutamine-expanded ATXN1 inclusions.

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Intercellular Propagation and Aggregate Seeding of Mutant Ataxin-1

Journal of Molecular Neuroscience ◽

10.1007/s12031-021-01944-1 ◽

2021 ◽

Author(s):

Haoyang Huang ◽

Nicholas Toker ◽

Eliza Burr ◽

Jeff Okoro ◽

Maia Moog ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Cell Model ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1 ◽

Pathogenic Role ◽

Tunneling Nanotubes ◽

Disease Propagation ◽

Intercellular Connections

AbstractIntercellular propagation of aggregated protein inclusions along actin-based tunneling nanotubes (TNTs) has been reported as a means of pathogenic spread in Alzheimer’s, Parkinson’s, and Huntington’s diseases. Propagation of oligomeric-structured polyglutamine-expanded ataxin-1 (Atxn1[154Q]) has been reported in the cerebellum of a Spinocerebellar ataxia type 1 (SCA1) knock-in mouse to correlate with disease propagation. In this study, we investigated whether a physiologically relevant polyglutamine-expanded ATXN1 protein (ATXN1[82Q]) could propagate intercellularly. Using a cerebellar-derived live cell model, we observed ATXN1 aggregates form in the nucleus, subsequently form in the cytoplasm, and finally, propagate to neighboring cells along actin-based intercellular connections. Additionally, we observed the facilitation of aggregate-resistant proteins into aggregates given the presence of aggregation-prone proteins within cells. Taken together, our results support a pathogenic role of intercellular propagation of polyglutamine-expanded ATXN1 inclusions.

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Role of the polyglutamine expansion in the pathogenesis of spinocerebellar ataxia type 1

Nature Clinical Practice Neurology ◽

10.1038/ncpneuro0818 ◽

2008 ◽

Vol 4 (7) ◽

pp. 350-350

Keyword(s):

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1 ◽

Polyglutamine Expansion

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Analysis of the role of ICAM-3 as a costimulatory molecule through a cell model: CAMY-1 and CAMY-2 (two CD50-negative Jurkat-T cell clones)

Immunology Letters ◽

10.1016/s0165-2478(97)87030-7 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 52

Author(s):

C Vilardell

Keyword(s):

T Cell ◽

Cell Model ◽

Costimulatory Molecule ◽

T Cell Clones ◽

Cell Clones ◽

Jurkat T Cell ◽

A Cell

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Faculty Opinions recommendation of Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1013653.191600 ◽

2003 ◽

Author(s):

Stuart Lipton

Keyword(s):

Spinocerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1

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PapRIV, a BV-2 microglial cell activating quorum sensing peptide

Scientific Reports ◽

10.1038/s41598-021-90030-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yorick Janssens ◽

Nathan Debunne ◽

Anton De Spiegeleer ◽

Evelien Wynendaele ◽

Marta Planas ◽

...

Keyword(s):

Quorum Sensing ◽

Cell Model ◽

Dependent Manner ◽

Communication Signals ◽

Gram Positive Bacteria ◽

A Cell ◽

Gastro Intestinal Tract

AbstractQuorum sensing peptides (QSPs) are bacterial peptides produced by Gram-positive bacteria to communicate with their peers in a cell-density dependent manner. These peptides do not only act as interbacterial communication signals, but can also have effects on the host. Compelling evidence demonstrates the presence of a gut-brain axis and more specifically, the role of the gut microbiota in microglial functioning. The aim of this study is to investigate microglial activating properties of a selected QSP (PapRIV) which is produced by Bacillus cereus species. PapRIV showed in vitro activating properties of BV-2 microglia cells and was able to cross the in vitro Caco-2 cell model and reach the brain. In vivo peptide presence was also demonstrated in mouse plasma. The peptide caused induction of IL-6, TNFα and ROS expression and increased the fraction of ameboid BV-2 microglia cells in an NF-κB dependent manner. Different metabolites were identified in serum, of which the main metabolite still remained active. PapRIV is thus able to cross the gastro-intestinal tract and the blood–brain barrier and shows in vitro activating properties in BV-2 microglia cells, hereby indicating a potential role of this quorum sensing peptide in gut-brain interaction.

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