scispace - formally typeset
Search or ask a question
Author

Harry C. Tjondro

Other affiliations: Tsinghua University
Bio: Harry C. Tjondro is an academic researcher from Macquarie University. The author has contributed to research in topics: Glycosylation & Azurophilic granule. The author has an hindex of 7, co-authored 11 publications receiving 360 citations. Previous affiliations of Harry C. Tjondro include Tsinghua University.

Papers
More filters
Journal ArticleDOI
30 Jul 2015-Nature
TL;DR: In this paper, the authors identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts.
Abstract: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people1, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

331 citations

Journal ArticleDOI
TL;DR: The literature supports the notion that PMPs are significant, yet still heavily under‐studied biomolecules in human glycobiology that serve essential functions and create structural heterogeneity not dissimilar to other human N‐glycoprotein types.
Abstract: Paucimannosidic proteins (PMPs) are bioactive glycoproteins carrying truncated α- or β-mannosyl-terminating asparagine (N)-linked glycans widely reported across the eukaryotic domain. Our understanding of human PMPs remains limited, despite findings documenting their existence and association with human disease glycobiology. This review comprehensively surveys the structures, biosynthetic routes and functions of PMPs across the eukaryotic kingdoms with the aim of synthesising an improved understanding on the role of protein paucimannosylation in human health and diseases. Convincing biochemical, glycoanalytical and biological data detail a vast structural heterogeneity and fascinating tissue- and subcellular-specific expression of PMPs within invertebrates and plants, often comprising multi-α1,3/6-fucosylation and β1,2-xylosylation amongst other glycan modifications and non-glycan substitutions e.g. O-methylation. Vertebrates and protists express less-heterogeneous PMPs typically only comprising variable core fucosylation of bi- and trimannosylchitobiose core glycans. In particular, the Manα1,6Manβ1,4GlcNAc(α1,6Fuc)β1,4GlcNAcβAsn glycan (M2F) decorates various human neutrophil proteins reportedly displaying bioactivity and structural integrity demonstrating that they are not degradation products. Less-truncated paucimannosidic glycans (e.g. M3F) are characteristic glycosylation features of proteins expressed by human cancer and stem cells. Concertedly, these observations suggest the involvement of human PMPs in processes related to innate immunity, tumorigenesis and cellular differentiation. The absence of human PMPs in diverse bodily fluids studied under many (patho)physiological conditions suggests extravascular residence and points to localised functions of PMPs in peripheral tissues. Absence of PMPs in Fungi indicates that paucimannosylation is common, but not universally conserved, in eukaryotes. Relative to human PMPs, the expression of PMPs in plants, invertebrates and protists is more tissue-wide and constitutive yet, similar to their human counterparts, PMP expression remains regulated by the physiology of the producing organism and PMPs evidently serve essential functions in development, cell-cell communication and host-pathogen/symbiont interactions. In most PMP-producing organisms, including humans, the N-acetyl-β-hexosaminidase isoenzymes and linkage-specific α-mannosidases are glycoside hydrolases critical for generating PMPs via N-acetylglucosaminyltransferase I (GnT-I)-dependent and GnT-I-independent truncation pathways. However, the identity and structure of many species-specific PMPs in eukaryotes, their biosynthetic routes, strong tissue- and development-specific expression, and diverse functions are still elusive. Deep exploration of these PMP features involving, for example, the characterisation of endogenous PMP-recognising lectins across a variety of healthy and N-acetyl-β-hexosaminidase-deficient human tissue types and identification of microbial adhesins reactive to human PMPs, are amongst the many tasks required for enhanced insight into the glycobiology of human PMPs. In conclusion, the literature supports the notion that PMPs are significant, yet still heavily under-studied biomolecules in human glycobiology that serve essential functions and create structural heterogeneity not dissimilar to other human N-glycoprotein types. Human PMPs should therefore be recognised as bioactive glycoproteins that are distinctly different from the canonical N-glycoprotein classes and which warrant a more dedicated focus in glycobiological research.

35 citations

Journal ArticleDOI
TL;DR: Novel functional roles of MPO glycans are reported, providing new insight into neutrophil-mediated immunity and molecular modelling revealed that hyper-truncated Asn355-glycans positioned in the MPO-ceruloplasmin interface are critical for uninterrupted inhibition.

26 citations

Journal ArticleDOI
TL;DR: This comprehensive neutrophil granule glycome map, the first of its kind, highlights novel granule-specific glycosylation features and is a crucial first step toward a better understanding of the mechanisms regulating protein glycosYLation during neutrophils granulopoiesis and a more detailed understanding of neutrophIL biology and function.

22 citations

Journal ArticleDOI
TL;DR: It is proposed that the highly dynamic ion-pairing network contributed to the tradeoff among βB1 solubility, stability, aggregatory propensity and function of protecting βA3.

18 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: It is shown that an AI agent using deep learning, and involving convolutional neural networks for diagnostics, risk stratification and treatment suggestions, accurately diagnoses and provides treatment decisions for congenital cataracts in an in silico test, a website-based study, in a ‘finding a needle in a haystack’ test and in a multihospital clinical trial.
Abstract: Using artificial intelligence (AI) to prevent and treat diseases is an ultimate goal in computational medicine. Although AI has been developed for screening and assisted decision-making in disease prevention and management, it has not yet been validated for systematic application in the clinic. In the context of rare diseases, the main strategy has been to build specialized care centres; however, these centres are scattered and their coverage is insufficient, which leaves a large proportion of rare-disease patients with inadequate care. Here, we show that an AI agent using deep learning, and involving convolutional neural networks for diagnostics, risk stratification and treatment suggestions, accurately diagnoses and provides treatment decisions for congenital cataracts in an in silico test, in a website-based study, in a ‘finding a needle in a haystack’ test and in a multihospital clinical trial. We also show that the AI agent and individual ophthalmologists perform equally well. Moreover, we have integrated the AI agent with a cloud-based platform for multihospital collaboration, designed to improve disease management for the benefit of patients with rare diseases. An artificial intelligence agent integrated with a cloud-based platform for multihospital collaboration performs equally as well as ophthalmologists in the diagnosis of congenital cataracts in a series of online tests and a multihospital clinical trial.

248 citations

Journal ArticleDOI
TL;DR: A critical appraisal of this increasingly popular hypothesis that abnormal forms of disease-associated proteins, such as tau or α-synuclein, physically move from neuron to neuron to induce disease progression seems both important and timely.
Abstract: There has been an explosion in the number of papers discussing the hypothesis of 'pathogenic spread' in neurodegenerative disease - the idea that abnormal forms of disease-associated proteins, such as tau or α-synuclein, physically move from neuron to neuron to induce disease progression. However, whether inter-neuronal spread of protein aggregates actually occurs in humans and, if so, whether it causes symptom onset remain uncertain. Even if pathogenic spread is proven in humans, it is unclear how much this would alter the specific therapeutic approaches that are in development. A critical appraisal of this increasingly popular hypothesis thus seems both important and timely.

230 citations

Journal ArticleDOI
06 Nov 2015-Science
TL;DR: The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract and partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo, suggesting an approach to treating cataracts by stabilizing α-crystallins.
Abstract: Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing α-crystallins.

191 citations

01 Jan 1980

172 citations

Journal ArticleDOI
TL;DR: New roles and new cofactors, as well as variations in structure and regulation of sHsps, have emerged, and current evidence suggests that smaller oligomers are more active chaperones.

161 citations