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

Eugenia D Trushina, Sandeep Rana, Cynthia T. McMurray, Duy H. Hua

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)73
Number of pages1
JournalBMC Neuroscience
Volume10
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

Pyrones
Corpus Striatum
Mutant Proteins
Huntington Disease
Phenotype
Neurons
Neurodegenerative Diseases
Alzheimer Disease
Clathrin
Endocytosis
Amyloid
Neuroglia
Huntingtin Protein
Animal Models
Cholesterol
Pathology
Mutation
Genes

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons. / Trushina, Eugenia D; Rana, Sandeep; McMurray, Cynthia T.; Hua, Duy H.

In: BMC Neuroscience, Vol. 10, 2009, p. 73.

Research output: Contribution to journalArticle

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