Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models

Front. Bioeng. Biotechnol.

Chan

et al. 2020

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Lignin-carbohydrate complex (LCC) is the biological macromolecule that has been demonstrated to exert multiple biological functions, including antioxidant, antiinflammation and anti-tumorigenesis, which support its broad application in the bioengineering field. However, it remains elusive the involvements of LCC in human neurological disorders, especially those with the overproduction of reactive oxygen species (ROS), such as spinocerebellar ataxias (SCAs). In this study, we found a previously undetermined anti-protein aggregation activity of LCC. Initially, two individual LCC preparations and carbohydrate-free lignin were isolated from the water-extracted waste residues of Chionanthus retusus (C. retusus) tender leaves. The chemical compositional analysis revealed that lignin (61.5%) is the predominant constituent in the lignin-rich LCC (LCC-L-CR), whereas the carbohydrate-rich LCC (LCC-C-CR) is mainly composed of carbohydrate (60.9%) with the xylan as the major constituent (42.1%). The NMR structural characterization showed that LCC-L-CR preparation is enriched in benzyl ether linkage, while phenyl glycoside is the predominant type of linkage in LCC-C-CR. Both LCC and lignin preparations showed antioxidant activities as exemplified by their abilities to scavenge free radicals in cultured mammalian cells and ROS in zebrafish. We further demonstrated a pronounced capability of LCC-L-CR in inhibiting the aggregation of expanded Ataxin-3, disease protein of SCA type 3, in human neuronal cells. Taken together, our study highlights the antioxidant and novel anti-protein aggregation activities of the C. retusus tender leaves-derived LCC.

Section: Effect Of Lcc and Lignin Preparations On Atxn3q71 Protein Agmentioning

confidence: 99%

Isolation and Identification of a Novel Anti-protein Aggregation Activity of Lignin-Carbohydrate Complex From Chionanthus retusus Leaves

Pei

Front. Bioeng. Biotechnol.

Chan

et al. 2020

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“…Through ubiquitinating and targeting the toxic insoluble polyQ proteins for degradation, FipoQ/FBXO33 may help with relieving several kinds of cellular stress, such as transcriptional dysregulation (Chen et al . ) and proteasomal impairment (Verhoef et al . ) induced by the accumulation of toxic, insoluble polyQ proteins.…”

Section: Discussionmentioning

confidence: 99%

FipoQ/FBXO33, a Cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein

Journal of Neurochemistry

Wong

Cheng

et al. 2019

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Polyglutamine (polyQ) diseases describe a group of progressive neurodegenerative disorders caused by the CAG triplet repeat expansion in the coding region of the disease genes. To date, nine such diseases, including spinocerebellar ataxia type 3 (SCA3), have been reported. The formation of SDS‐insoluble protein aggregates in neurons causes cellular dysfunctions, such as impairment of the ubiquitin‐proteasome system, and contributes to polyQ pathologies. Recently, the E3 ubiquitin ligases, which govern substrate specificity of the ubiquitin‐proteasome system, have been implicated in polyQ pathogenesis. The Cullin (Cul) proteins are major components of Cullin‐RING ubiquitin ligases (CRLs) complexes that are evolutionarily conserved in the Drosophila genome. In this study, we examined the effect of individual Culs on SCA3 pathogenesis and found that the knockdown of Cul1 expression enhances SCA3‐induced neurodegeneration and reduces the solubility of expanded SCA3‐polyQ proteins. The F‐box proteins are substrate receptors of Cul1‐based CRL. We further performed a genetic modifier screen of the 19 Drosophila F‐box genes and identified F‐box involved in polyQ pathogenesis (FipoQ) as a genetic modifier of SCA3 degeneration that modulates the ubiquitination and solubility of expanded SCA3‐polyQ proteins. In the human SK‐N‐MC cell model, we identified that F‐box only protein 33 (FBXO33) exerts similar functions as FipoQ in modulating the ubiquitination and solubility of expanded SCA3‐polyQ proteins. Taken together, our study demonstrates that Cul1‐based CRL and its associated F‐box protein, FipoQ/FBXO33, modify SCA3 protein toxicity. These findings will lead to a better understanding of the disease mechanism of SCA3 and provide insights for developing treatments against SCA3. Cover Image for this issue: doi: .

“…Details of the assay were previously described (6). In a typical procedure, fly heads were cut and observed under light microscopy (Olympus BX51, Tokyo, Japan) with a ϫ60 oil objective.…”

Section: Drosophila Pseudopupil Assaymentioning

confidence: 99%

“…The primary rat cortical neurons were prepared as described previously (6). In brief, the cells were isolated from E18 rat embryos and cultured at 24-well plates pre-coated with poly-D-lysine (Sigma).…”

Section: Primary Rat Cortical Neuronsmentioning

confidence: 99%

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AQAMAN, a bisamidine-based inhibitor of toxic protein inclusions in neurons, ameliorates cytotoxicity in polyglutamine disease models

Hong

Koon

Journal of Biological Chemistry

et al. 2019

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Edited by Joseph M. Jez Polyglutamine (polyQ) diseases are a group of dominantly inherited neurodegenerative disorders caused by the expansion of an unstable CAG repeat in the coding region of the affected genes. Hallmarks of polyQ diseases include the accumulation of misfolded protein aggregates, leading to neuronal degeneration and cell death. PolyQ diseases are currently incurable, highlighting the urgent need for approaches that inhibit the formation of disaggregate cytotoxic polyQ protein inclusions. Here, we screened for bisamidine-based inhibitors that can inhibit neuronal polyQ protein inclusions. We demonstrated that one inhibitor, AQAMAN, prevents polyQ protein aggregation and promotes de-aggregation of self-assembled polyQ proteins in several models of polyQ diseases. Using immunocytochemistry, we found that AQAMAN significantly reduces polyQ protein aggregation and specifically suppresses polyQ protein-induced cell death. Using a recombinant and purified polyQ protein (thioredoxin-Huntingtin-Q46), we further demonstrated that AQAMAN interferes with polyQ self-assembly, preventing polyQ aggregation, and dissociates preformed polyQ aggregates in a cell-free system. Remarkably, AQAMAN feeding of Drosophila expressing expanded polyQ disease protein suppresses polyQ-induced neurodegeneration in vivo. In addition, using inhibitors and activators of the autophagy pathway, we demonstrated that AQAMAN's cytoprotective effect against polyQ toxicity is autophagy-dependent. In summary, we have identified AQAMAN as a potential therapeutic for combating polyQ protein toxicity in polyQ diseases. Our findings further highlight the importance of the autophagy pathway in clearing harmful polyQ proteins.