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


CONCLUSIONS
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.
Trushina
Eugenia
E
Department of Chemistry, CBC Building, Kansas State University, Manhattan, KS 66506, USA. trushina.eugenia@mayo.edu
Rana
Sandeep
S
McMurray
Cynthia T
CT
Hua
Duy H
DH
D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D004705:Endocytosis / Q000187:drug effects; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002479:Inclusion Bodies / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011753:Pyrones; D002784:Cholesterol