Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 5, Pages 2728-2743Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.588608
Keywords
Bioinformatics; Brain-derived Neurotrophic Factor (BDNF); Huntington Disease; Mitochondria; Neurodegenerative Disease; Amitriptyline; Motor Function; mHTT
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Funding
- National Institutes of Health Intramural Research Program of the NIA
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Background: Etiology of Huntington disease (HD) is related to the overproduction of mutant huntingtin (mHTT) protein. Results: Amitriptyline improved motor symptoms via decreasing mHTT protein expression, improving neurotrophin signaling, and enhancing mitochondrial functions in HD mice. Conclusion: Amitriptyline demonstrated beneficial effects in HD mice. Significance: Amitriptyline has therapeutic potential in treating HD. Huntington disease (HD) is a neurodegenerative disorder characterized by progressive motor impairment and cognitive alterations. Hereditary HD is primarily caused by the expansion of a CAG trinucleotide repeat in the huntingtin (Htt) gene, which results in the production of mutant huntingtin protein (mHTT) with an expanded amino-terminal polyglutamine (poly(Q)) stretch. Besides pathological mHTT aggregation, reduced brain-derived neurotrophic factor (BDNF) levels, impaired neurotrophin signaling, and compromised mitochondrial functions also contribute to the deleterious progressive etiology of HD. As a well tolerated Food and Drug Administration-approved antidepressant, amitriptyline (AMI) has shown efficacy in treating neurodegenerative murine models via potentiation of BDNF levels and amelioration of alterations in neurotrophin signaling pathways. In this study, we observed profound improvements in the motor coordination of AMI-treated N171-82Q HD model mice. The beneficial effects of AMI treatment were associated with its ability to reduce mHTT aggregation, potentiation of the BDNF-TrkB signaling system, and support of mitochondrial integrity and functionality. Our study not only provides preclinical evidence for the therapeutic potency of AMI in treating HD, but it also represents an important example of the usefulness of additional pharmacogenomic profiling of pre-existing drugs for novel therapeutic effects with often intractable pathological scenarios.
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