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Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons.

Trushina E, Rana S, McMurray CT, Hua DH - BMC Neurosci (2009)

Bottom Line: Most data suggest that polyglutamine-mediated aggregation associated with expression of mutant huntingtin protein (mhtt) contributes to the pathology.Suppression of aggregation is accepted as one of the markers of successful therapeutic approaches.TP compounds effectively inhibit aggregation caused by mhtt in neurons and glial cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA. trushina.eugenia@mayo.edu

ABSTRACT

Background: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion mutation in the coding region of a novel gene. The mechanism of HD is unknown. Most data suggest that polyglutamine-mediated aggregation associated with expression of mutant huntingtin protein (mhtt) contributes to the pathology. However, recent studies have identified early cellular dysfunctions that preclude aggregate formation. Suppression of aggregation is accepted as one of the markers of successful therapeutic approaches. Previously, we demonstrated that tricyclic pyrone (TP) compounds efficiently inhibited formation of amyloid-beta (Abeta) aggregates in cell and mouse models representing Alzheimer's Disease (AD). In the present study, we aimed to determine whether TP compounds could prevent aggregation and restore early cellular defects in primary embryonic striatal neurons from animal model representing HD.

Results: TP compounds effectively inhibit aggregation caused by mhtt in neurons and glial cells. Treatment with TP compounds also alleviated cholesterol accumulation and restored clathrin-independent endocytosis in HD neurons.

Conclusion: We have found that TP compounds not only blocked mhtt-induced aggregation, but also alleviated early cellular dysfunctions that preclude aggregate formation. Our data suggest TP molecules may be used as lead compounds for prevention or treatment of multiple neurodegenerative diseases including HD and AD.

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Chemical structures of TP compounds utilized in the study and synthesis of compound TP4. TFA – trifluoracetic acid; THF – tetrahydrofuran; HMPA – hexamethylphophoramide.
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Figure 1: Chemical structures of TP compounds utilized in the study and synthesis of compound TP4. TFA – trifluoracetic acid; THF – tetrahydrofuran; HMPA – hexamethylphophoramide.

Mentions: We have previously synthesized and examined the biological activity of a number of tricyclic pyrone (TP) analogs and found that TP compounds directly bind to and inhibit formation of amyloid-β (Aβ) aggregates in cell model representing Alzheimer's Disease (AD) [14-16]. Moreover, 2-week treatment with CP2 (Figure 1A) dramatically reduced formation of non-fibrillar and fibrillar Aβ oligomers in vivo in mouse model representing familial AD [16]. Thus, TPs represent a promising class of compounds with anti-aggregate properties. However, whether TP compounds could prevent aggregate formation in other neurodegenerative disorders has not been studied. It is also unknown whether TP compounds could ameliorate earlier cellular defects that preclude aggregate formation in the cells.


Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons.

Trushina E, Rana S, McMurray CT, Hua DH - BMC Neurosci (2009)

Chemical structures of TP compounds utilized in the study and synthesis of compound TP4. TFA – trifluoracetic acid; THF – tetrahydrofuran; HMPA – hexamethylphophoramide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2719645&req=5

Figure 1: Chemical structures of TP compounds utilized in the study and synthesis of compound TP4. TFA – trifluoracetic acid; THF – tetrahydrofuran; HMPA – hexamethylphophoramide.
Mentions: We have previously synthesized and examined the biological activity of a number of tricyclic pyrone (TP) analogs and found that TP compounds directly bind to and inhibit formation of amyloid-β (Aβ) aggregates in cell model representing Alzheimer's Disease (AD) [14-16]. Moreover, 2-week treatment with CP2 (Figure 1A) dramatically reduced formation of non-fibrillar and fibrillar Aβ oligomers in vivo in mouse model representing familial AD [16]. Thus, TPs represent a promising class of compounds with anti-aggregate properties. However, whether TP compounds could prevent aggregate formation in other neurodegenerative disorders has not been studied. It is also unknown whether TP compounds could ameliorate earlier cellular defects that preclude aggregate formation in the cells.

Bottom Line: Most data suggest that polyglutamine-mediated aggregation associated with expression of mutant huntingtin protein (mhtt) contributes to the pathology.Suppression of aggregation is accepted as one of the markers of successful therapeutic approaches.TP compounds effectively inhibit aggregation caused by mhtt in neurons and glial cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA. trushina.eugenia@mayo.edu

ABSTRACT

Background: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion mutation in the coding region of a novel gene. The mechanism of HD is unknown. Most data suggest that polyglutamine-mediated aggregation associated with expression of mutant huntingtin protein (mhtt) contributes to the pathology. However, recent studies have identified early cellular dysfunctions that preclude aggregate formation. Suppression of aggregation is accepted as one of the markers of successful therapeutic approaches. Previously, we demonstrated that tricyclic pyrone (TP) compounds efficiently inhibited formation of amyloid-beta (Abeta) aggregates in cell and mouse models representing Alzheimer's Disease (AD). In the present study, we aimed to determine whether TP compounds could prevent aggregation and restore early cellular defects in primary embryonic striatal neurons from animal model representing HD.

Results: TP compounds effectively inhibit aggregation caused by mhtt in neurons and glial cells. Treatment with TP compounds also alleviated cholesterol accumulation and restored clathrin-independent endocytosis in HD neurons.

Conclusion: We have found that TP compounds not only blocked mhtt-induced aggregation, but also alleviated early cellular dysfunctions that preclude aggregate formation. Our data suggest TP molecules may be used as lead compounds for prevention or treatment of multiple neurodegenerative diseases including HD and AD.

Show MeSH
Related in: MedlinePlus