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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

PolyQ-GFP protein distribution, survival rate and bending frequency in C. elegans Huntington disease model, carrying different length of polyQ (Q16 and Q148).Notes: (A) Aggregates can be seen all over the body wall muscle cells in Q148 worms. (B) The arrows indicated magnification of the aggregates existing as “dots” that gather to the form of “strings” in Q148 worms. (C) The average life spans were: Q16: 5.44 h, Q148: 4.95 h**. (D) The average bending frequencies were: Q16: 32.33/20 s, Q148: 24.36/20 s. (**P<0.001).Abbreviations: PolyQ, polyglutamine; GFP, green fluorescent protein.
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f2-dddt-10-1443: PolyQ-GFP protein distribution, survival rate and bending frequency in C. elegans Huntington disease model, carrying different length of polyQ (Q16 and Q148).Notes: (A) Aggregates can be seen all over the body wall muscle cells in Q148 worms. (B) The arrows indicated magnification of the aggregates existing as “dots” that gather to the form of “strings” in Q148 worms. (C) The average life spans were: Q16: 5.44 h, Q148: 4.95 h**. (D) The average bending frequencies were: Q16: 32.33/20 s, Q148: 24.36/20 s. (**P<0.001).Abbreviations: PolyQ, polyglutamine; GFP, green fluorescent protein.

Mentions: In the C. elegans model, we established that polyQ-GFP proteins tagged with GFP could be observed directly in muscle cells under a fluorescence microscope. The animals expressing the normal polyQ repeat, Q16, showed smooth green lines in both the ventral and the dorsal muscle cells, while Q148-expressing nematodes showed discontinuous foci in muscle cells throughout their life span.31 The foci were mHtt aggregations, presenting as dots or even fibril-like strings (Figure 2A and B). In contrast to the relatively normal presentation of Q16-expressing worms, Q148-expressing worms were much shorter at the same stage of development (Figure 2A). They also had a shorter life span and weakened motility. The life span of Q148 worms decreased under heat stress, and total mortality was observed after heat treatment for 7 hours, whereas 30% of Q16 worms remained alive at that time (Figure 2C). Furthermore, Q148 worms also had a defect in bending, which can be reduced up to 70% in frequency in contrast to Q16 worms (Figure 2D).


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)

PolyQ-GFP protein distribution, survival rate and bending frequency in C. elegans Huntington disease model, carrying different length of polyQ (Q16 and Q148).Notes: (A) Aggregates can be seen all over the body wall muscle cells in Q148 worms. (B) The arrows indicated magnification of the aggregates existing as “dots” that gather to the form of “strings” in Q148 worms. (C) The average life spans were: Q16: 5.44 h, Q148: 4.95 h**. (D) The average bending frequencies were: Q16: 32.33/20 s, Q148: 24.36/20 s. (**P<0.001).Abbreviations: PolyQ, polyglutamine; GFP, green fluorescent protein.
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-10-1443: PolyQ-GFP protein distribution, survival rate and bending frequency in C. elegans Huntington disease model, carrying different length of polyQ (Q16 and Q148).Notes: (A) Aggregates can be seen all over the body wall muscle cells in Q148 worms. (B) The arrows indicated magnification of the aggregates existing as “dots” that gather to the form of “strings” in Q148 worms. (C) The average life spans were: Q16: 5.44 h, Q148: 4.95 h**. (D) The average bending frequencies were: Q16: 32.33/20 s, Q148: 24.36/20 s. (**P<0.001).Abbreviations: PolyQ, polyglutamine; GFP, green fluorescent protein.
Mentions: In the C. elegans model, we established that polyQ-GFP proteins tagged with GFP could be observed directly in muscle cells under a fluorescence microscope. The animals expressing the normal polyQ repeat, Q16, showed smooth green lines in both the ventral and the dorsal muscle cells, while Q148-expressing nematodes showed discontinuous foci in muscle cells throughout their life span.31 The foci were mHtt aggregations, presenting as dots or even fibril-like strings (Figure 2A and B). In contrast to the relatively normal presentation of Q16-expressing worms, Q148-expressing worms were much shorter at the same stage of development (Figure 2A). They also had a shorter life span and weakened motility. The life span of Q148 worms decreased under heat stress, and total mortality was observed after heat treatment for 7 hours, whereas 30% of Q16 worms remained alive at that time (Figure 2C). Furthermore, Q148 worms also had a defect in bending, which can be reduced up to 70% in frequency in contrast to Q16 worms (Figure 2D).

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