ORCID Profile
0000-0002-4931-8445
Current Organisations
University of Queensland
,
University of California, San Diego
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Publisher: The Royal Society
Date: 09-2022
DOI: 10.1098/RSOB.220187
Abstract: Splicing factor proline- and glutamine-rich (SFPQ) is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating centre (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a second zinc-binding site revealed by the 1.83 Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.
Publisher: American Astronomical Society
Date: 10-03-2007
DOI: 10.1086/510896
Publisher: American Society for Cell Biology (ASCB)
Date: 2020
Abstract: The anterograde trafficking of BACE1 and the potential processing of amyloid precursor protein along the secretory pathway remain poorly defined. Our findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.
Publisher: American Physical Society (APS)
Date: 06-12-2021
Publisher: IEEE
Date: 12-2017
Publisher: Oxford University Press (OUP)
Date: 09-10-2018
Publisher: American Astronomical Society
Date: 09-05-2017
Publisher: Springer Science and Business Media LLC
Date: 23-11-2011
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Teresa Mineo.