ORCID Profile
0000-0003-4064-3599
Current Organisation
The University of Auckland
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Publisher: Cold Spring Harbor Laboratory
Date: 10-02-2023
DOI: 10.1101/2023.02.10.527924
Abstract: Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2 -linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non- UBQLN2 -linked (sporadic) ALS cases, and eight non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates, and aggregates containing both proteins in regions of interest to determine how UBQLN2 -linked and non- UBQLN2 -linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate, and are abundant in the hippoc al formation, spinal cord, all tested regions of neocortex, medulla, and substantia nigra in UBQLN2 -linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2 -linked ALS/FTD. While ubiquilin 2 deposition in frontotemporal regions may enhance cognitive risk in UBQLN2 -linked cases, ubiquilin 2 is deposited mainly in clinically unaffected regions throughout the CNS such that overall symptomology in these cases maps best to the aggregation of TDP-43.
Publisher: Elsevier BV
Date: 2013
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-05-2017
DOI: 10.1126/SCITRANSLMED.AAD9157
Abstract: Annexin A11 mutations, implicated in ALS, prevent binding to calcyclin and induce the formation of cytoplasmic inclusions.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.NEUROBIOLAGING.2016.06.019
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which causes progressive and eventually fatal loss of motor function. Here, we describe genetic and pathologic characterization of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats (DPRs), and ubiquilin. We identified 2 cases with C9ORF72 repeat expansions. Both harbored phosphorylated TDP-43 and DPR inclusions. We show that DPR inclusions can incorporate or occur independently of ubiquilin. We also identified 1 case with a UBQLN2 mutation, which showed phosphorylated TDP-43 and characteristic ubiquilin protein inclusions. This is the first study of ALS genetics in New Zealand, adding New Zealand to the growing list of countries in which C9ORF72 repeat expansion and UBQLN2 mutations are detected in ALS cases.
Publisher: Public Library of Science (PLoS)
Date: 17-01-2012
Publisher: Springer Science and Business Media LLC
Date: 05-02-2015
Publisher: Cold Spring Harbor Laboratory
Date: 12-01-2022
DOI: 10.1101/2022.01.12.475792
Abstract: Mutations in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippoc us, and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial ALS or FTD cases not caused by UBQLN2 mutations, particularly C9orf72 -linked cases. This makes the mechanistic role of ubiquilin 2 mutations and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 41 genotypically erse ALS cases with or without FTD, including five cases with UBQLN2 variants (resulting in p.S222G, p.P497H, p.P506S, and two cases with p.T487I). Using multiplexed (5-label) fluorescent immunohistochemistry, we mapped the co-localisation of ubiquilin 2 with phosphorylated TDP-43 (pTDP-43), dipeptide repeat aggregates, and p62, in the hippoc us of controls (n=5), or ALS with or without FTD in sporadic (n=20), unknown familial (n=3), SOD1 -linked (n=1), FUS -linked (n=1), C9orf72 -linked (n=5), and UBQLN2 -linked (n=5) cases. We differentiate between i) ubiquilin 2 aggregation together with pTDP-43 or dipeptide repeat proteins, and ii) ubiquilin 2 self-aggregation promoted by UBQLN2 gene mutations that cause ALS/FTD. Overall, we describe a hippoc al protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in ALS with or without FTD, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2 -linked disease.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2015
Publisher: Springer Science and Business Media LLC
Date: 12-05-2013
DOI: 10.1038/NCB2744
Abstract: In cells, a complex network of proteins regulates the dynamic growth of microtubules that is essential for ision and migration. In vitro approaches with purified components have so far been unable to reconstitute fast microtubule growth observed in vivo . Here we show that two well-studied plus-end-binding proteins-end-tracking protein EB1 and microtubule polymerase XMAP215-act together to strongly promote microtubule growth to cellular rates. Unexpectedly, the combined effects of XMAP215 and EB1 are highly synergistic, with acceleration of growth well beyond the product of the in idual effects of either protein. The synergistic growth promotion does not rely on any of the canonical EB1 interactions, suggesting an allosteric interaction through the microtubule end. This hypothesis is supported by the finding that taxol and XMAP215, which have non-overlapping binding sites on tubulin, also act synergistically on growth. The increase in growth rates is accompanied by a strong enhancement of microtubule catastrophe by EB1, thereby rendering the fast and dynamic microtubule behaviour typically observed in cells.
Publisher: Proceedings of the National Academy of Sciences
Date: 31-01-2011
Abstract: XMAP215/Dis1 family proteins positively regulate microtubule growth. Repeats at their N termini, called TOG domains, are important for this function. While TOG domains directly bind tubulin dimers, it is unclear how this interaction translates to polymerase activity. Understanding the functional roles of TOG domains is further complicated by the fact that the number of these domains present in the proteins of different species varies. Here, we take advantage of a recent crystal structure of the third TOG domain from Caenorhabditis elegans , Zyg9, and mutate key residues in each TOG domain of XMAP215 that are predicted to be important for interaction with the tubulin heterodimer. We determined the contributions of the in idual TOG domains to microtubule growth. We show that the TOG domains are absolutely required to bind free tubulin and that the domains differentially contribute to XMAP215’s overall affinity for free tubulin. The mutants’ overall affinity for free tubulin correlates well with polymerase activity. Furthermore, we demonstrate that an additional basic region is important for targeting to the microtubule lattice and is critical for XMAP215 to function at physiological concentrations. Using this information, we have engineered a “bonsai” protein, with two TOG domains and a basic region, that has almost full polymerase activity.
Publisher: Public Library of Science (PLoS)
Date: 20-03-2014
Publisher: Oxford University Press (OUP)
Date: 07-03-2013
DOI: 10.1093/HMG/DDT117
Publisher: Public Library of Science (PLoS)
Date: 23-10-2009
Publisher: Elsevier BV
Date: 02-2013
Publisher: The Company of Biologists
Date: 2014
DOI: 10.1242/JCS.140087
Abstract: TARDBP (TDP-43) is the major pathological protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Large TDP-43 aggregates decorated by degradation adaptor proteins are seen in the cytoplasm of remaining neurons in patients post mortem. TDP-43 accumulation, and ALS-linked mutations within degradation pathways, implicates failed TDP-43 clearance as a primary disease mechanism. Here we report the differential roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of TDP-43. We have investigated the effects of UPS and autophagy inhibitors on the degradation, localisation and mobility of soluble and insoluble TDP-43. We find that soluble TDP-43 is degraded primarily by the UPS, while aggregated TDP-43 clearance requires autophagy. Cellular macroaggregates, which recapitulate many pathological features of patient aggregates, are reversible when both the UPS and autophagy are competent. Their clearance involves the autophagic removal of oligomeric TDP-43. We speculate that in addition to age-related decline, a second hit in the UPS or autophagy pathways drives the accumulation of TDP-43 in ALS and FTD. Therapies for clearing excess TDP-43 should therefore be targeted to a combination of these pathways.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-06-2020
Abstract: Mutations in UBQLN2 cause amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). UBQLN2 regulates proteostasis by clearing misfolded proteins from cells through the proteasome and autophagy degradation pathways. Here, we report on defects in autophagy that results from knockout or expression of WT and ALS/FTD mutant UBQLN2 proteins in cells and mice. We show that loss of UBQLN2 reduces expression of ATP6v1g1, a critical subunit of the ATPase pump that regulates vacuolar acidification and is required for the maturation of autophagosomes. We show that WT but not ALS/FTD mutant UBQLN2 proteins can rescue the acidification defect. Furthermore, WT but not ALS/FTD mutant UBQLN2 proteins bind and stimulate ATP6v1g1 biogenesis, suggesting an important role played by UBQLN2 in V-ATPase regulation.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.PNEUROBIO.2022.102229
Abstract: Our understanding of amyotrophic lateral sclerosis and frontotemporal dementia has advanced dramatically since the discovery of cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions as the hallmark pathology of these neurodegenerative diseases. Recent studies have provided insights into the physiological function of TDP-43 as an essential DNA-/RNA-modulating protein, and the triggers and consequences of TDP-43 dysfunction and aggregation. The formation of TDP-43 pathology is a progressive process, involving the generation of multiple distinct protein species, each with varying biophysical properties and roles in neurodegeneration. Here, we explore how the pathogenic changes to TDP-43, including mislocalisation, misfolding, aberrant liquid-liquid phase separation, stress granule assembly, oligomerisation, and post-translational modification, drive disease-associated aggregation in TDP-43 proteinopathies. We highlight how pathological TDP-43 species are formed and contribute to cellular dysfunction and toxicity, via both loss-of-function and gain-of-function mechanisms. We also review the role of protein homeostasis mechanisms, namely the ubiquitin proteasome system, autophagy-lysosome pathway, heat-shock response, and chaperone-mediated autophagy, in combating TDP-43 aggregation and discuss how their dysfunction likely promotes disease pathogenesis and progression. Finally, we evaluate pre-clinical studies aimed at enhancing TDP-43 protein clearance via these mechanisms and provide insight on promising strategies for future therapeutic advances. Harnessing the mechanisms that protect against or ameliorate TDP-43 pathology presents promising opportunities for developing disease-modifying treatments for these neurodegenerative diseases.
Publisher: Elsevier BV
Date: 03-2015
Publisher: Wiley
Date: 27-03-2013
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.CELL.2011.10.037
Abstract: Microtubules are dynamic filaments whose ends alternate between periods of slow growth and rapid shortening as they explore intracellular space and move organelles. A key question is how regulatory proteins modulate catastrophe, the conversion from growth to shortening. To study this process, we reconstituted microtubule dynamics in the absence and presence of the kinesin-8 Kip3 and the kinesin-13 MCAK. Surprisingly, we found that, even in the absence of the kinesins, the microtubule catastrophe frequency depends on the age of the microtubule, indicating that catastrophe is a multistep process. Kip3 slowed microtubule growth in a length-dependent manner and increased the rate of aging. In contrast, MCAK eliminated the aging process. Thus, both kinesins are catastrophe factors Kip3 mediates fine control of microtubule length by narrowing the distribution of maximum lengths prior to catastrophe, whereas MCAK promotes rapid restructuring of the microtubule cytoskeleton by making catastrophe a first-order random process.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Elsevier BV
Date: 10-2014
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2022
End Date: 2025
Funder: Marsden Fund
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