ORCID Profile
0000-0002-6537-1166
Current Organisation
University of Queensland
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Publisher: Wiley
Date: 30-01-2017
DOI: 10.1111/TRA.12465
Abstract: The intracellular trafficking and proteolytic processing of the membrane-bound amyloid precursor protein (APP) are coordinated events leading to the generation of pathogenic amyloid-beta (Aβ) peptides. The membrane transport of newly synthesized APP from the Golgi to the endolysosomal system is not well defined, yet it is likely to be critical for regulating its processing by β-secretase (BACE1) and γ-secretase. Here, we show that the majority of newly synthesized APP is transported from the trans-Golgi network (TGN) directly to early endosomes and then subsequently to the late endosomes/lysosomes with very little transported to the cell surface. We show that Arl5b, a small G protein localized to the TGN, and AP4 are essential for the post-Golgi transport of APP to early endosomes. Arl5b is physically associated with AP4 and is required for the recruitment of AP4, but not AP1, to the TGN. Depletion of either Arl5b or AP4 results in the accumulation of APP, but not BACE1, in the Golgi, and an increase in APP processing and Aβ secretion. These findings demonstrate that APP is erted from BACE1 at the TGN for direct transport to early endosomes and that the TGN represents a site for APP processing with the subsequent secretion of Aβ.
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 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: MDPI AG
Date: 03-06-2019
DOI: 10.3390/CELLS8060531
Abstract: The trans-Golgi network (TGN) is responsible for selectively recruiting newly synthesized cargo into transport carriers for delivery to their appropriate destination. In addition, the TGN is responsible for receiving and recycling cargo from endosomes. The membrane organization of the TGN facilitates the sorting of cargoes into distinct populations of transport vesicles. There have been significant advances in defining the molecular mechanism involved in the recognition of membrane cargoes for recruitment into different populations of transport carriers. This machinery includes cargo adaptors of the adaptor protein (AP) complex family, and monomeric Golgi-localized γ ear-containing Arf-binding protein (GGA) family, small G proteins, coat proteins, as well as accessory factors to promote budding and fission of transport vesicles. Here, we review this literature with a particular focus on the transport pathway(s) mediated by the in idual cargo adaptors and the cargo motifs recognized by these adaptors. Defects in these cargo adaptors lead to a wide variety of diseases.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.BBAMEM.2018.11.013
Abstract: Alzheimer's disease (AD) is characterized by progressive accumulation of misfolded proteins, which form senile plaques and neurofibrillary tangles, and the release of inflammatory mediators by innate immune responses. β-Amyloid peptide (Aβ) is derived from sequential processing of the amyloid precursor protein (APP) by membrane-bound proteases, namely the β-secretase, BACE1, and γ-secretase. Membrane trafficking plays a key role in the regulation of APP processing as both APP and the processing secretases traffic along distinct pathways. Genome wide sequencing studies have identified several AD susceptibility genes which regulate membrane trafficking events. To understand the pathogenesis of AD it is critical that the cell biology of APP and Aβ production in neurons is well defined. This review discusses recent advances in unravelling the membrane trafficking events associated with the production of Aβ, and how AD susceptible alleles may perturb the sorting and transport of APP and BACE1. Mechanisms whereby inflammation may influence APP processing are also considered.
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2022
DOI: 10.1101/2022.03.10.483757
Abstract: 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 center (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a secondary zinc-binding site revealed by the 1.83Å 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: Elsevier BV
Date: 07-2021
Publisher: Elsevier BV
Date: 02-2019
No related grants have been discovered for Jing Zhi Anson Tan.