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Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.

Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, Liang F, Huang Y, Lu X, Li S, Zhou J, Burgunder JM, Pang J, Pei Z - Drug Des Devel Ther (2016)

Bottom Line: Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases.Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds.Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangzhou Center, Chinese Huntington's Disease Network, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT
Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

No MeSH data available.


Related in: MedlinePlus

Effect of xyloketal derivatives on Htt aggregation.Notes: (A) Worms treated with 100 μM DMSO and other 100 μM compounds (1~6); both the number and the intensity of green foci decreased in drug-treated groups. Fewer fibril-like strings could be observed in drug-treated groups. (B) Aggregate foci numbers on treatment with the various compounds were: 1 (78.6**), 2 (86.6), 3 (94.9), 4 (83.8*), 5 (84.1*), 6 (84.9*) vs DMSO (93.6) respectively. (C) The western blot of worms treated by DMSO ans other drugs. *P<0.05; **P<0.001.Abbreviations: DMSO, dimethyl sulfoxide; Htt, huntingtin.
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f4-dddt-10-1443: Effect of xyloketal derivatives on Htt aggregation.Notes: (A) Worms treated with 100 μM DMSO and other 100 μM compounds (1~6); both the number and the intensity of green foci decreased in drug-treated groups. Fewer fibril-like strings could be observed in drug-treated groups. (B) Aggregate foci numbers on treatment with the various compounds were: 1 (78.6**), 2 (86.6), 3 (94.9), 4 (83.8*), 5 (84.1*), 6 (84.9*) vs DMSO (93.6) respectively. (C) The western blot of worms treated by DMSO ans other drugs. *P<0.05; **P<0.001.Abbreviations: DMSO, dimethyl sulfoxide; Htt, huntingtin.

Mentions: The number of foci in body muscle cells was assessed in late-L4-stage worms. The protective effect of compounds 1, 4, 5, and 6 was accompanied by a reduction of aggregation in muscle cells. After 60 hours of treatment, the numbers of green foci located along the body wall cells decreased and fibril-like strings significantly reduced. The intensity of foci also weakened after treatment (Figure 4A). All these compounds diminished the aggregate foci to varying degrees, with 1 being the most effective. Statistical analysis revealed that compound 1 could decrease the aggregation by 20%, while compounds 4, 5, and 6 showed an average reduction of 10% (Figure 4B). However, compounds 2 and 3 showed no significant effect in the aggregation assay, which could suggest a different mechanism for their protective effects. Overexpression of mHtt has been known to change the chaperone activity and the global proteostasis network of C. elegans, and xyloketals might have protective properties mediated through these pathways.35 Therefore, it is possible that compounds 2 and 3 protected the muscle cells by alerting the proteostasis network either singularly or in parallel with other molecules to clear aggregates. Western blotting showed that the formation of mHtt aggregates was affected by treatment with different compounds (Figure 4C).


Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.

Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, Liang F, Huang Y, Lu X, Li S, Zhou J, Burgunder JM, Pang J, Pei Z - Drug Des Devel Ther (2016)

Effect of xyloketal derivatives on Htt aggregation.Notes: (A) Worms treated with 100 μM DMSO and other 100 μM compounds (1~6); both the number and the intensity of green foci decreased in drug-treated groups. Fewer fibril-like strings could be observed in drug-treated groups. (B) Aggregate foci numbers on treatment with the various compounds were: 1 (78.6**), 2 (86.6), 3 (94.9), 4 (83.8*), 5 (84.1*), 6 (84.9*) vs DMSO (93.6) respectively. (C) The western blot of worms treated by DMSO ans other drugs. *P<0.05; **P<0.001.Abbreviations: DMSO, dimethyl sulfoxide; Htt, huntingtin.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835117&req=5

f4-dddt-10-1443: Effect of xyloketal derivatives on Htt aggregation.Notes: (A) Worms treated with 100 μM DMSO and other 100 μM compounds (1~6); both the number and the intensity of green foci decreased in drug-treated groups. Fewer fibril-like strings could be observed in drug-treated groups. (B) Aggregate foci numbers on treatment with the various compounds were: 1 (78.6**), 2 (86.6), 3 (94.9), 4 (83.8*), 5 (84.1*), 6 (84.9*) vs DMSO (93.6) respectively. (C) The western blot of worms treated by DMSO ans other drugs. *P<0.05; **P<0.001.Abbreviations: DMSO, dimethyl sulfoxide; Htt, huntingtin.
Mentions: The number of foci in body muscle cells was assessed in late-L4-stage worms. The protective effect of compounds 1, 4, 5, and 6 was accompanied by a reduction of aggregation in muscle cells. After 60 hours of treatment, the numbers of green foci located along the body wall cells decreased and fibril-like strings significantly reduced. The intensity of foci also weakened after treatment (Figure 4A). All these compounds diminished the aggregate foci to varying degrees, with 1 being the most effective. Statistical analysis revealed that compound 1 could decrease the aggregation by 20%, while compounds 4, 5, and 6 showed an average reduction of 10% (Figure 4B). However, compounds 2 and 3 showed no significant effect in the aggregation assay, which could suggest a different mechanism for their protective effects. Overexpression of mHtt has been known to change the chaperone activity and the global proteostasis network of C. elegans, and xyloketals might have protective properties mediated through these pathways.35 Therefore, it is possible that compounds 2 and 3 protected the muscle cells by alerting the proteostasis network either singularly or in parallel with other molecules to clear aggregates. Western blotting showed that the formation of mHtt aggregates was affected by treatment with different compounds (Figure 4C).

Bottom Line: Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases.Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds.Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangzhou Center, Chinese Huntington's Disease Network, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT
Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

No MeSH data available.


Related in: MedlinePlus