期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 39, 页码 16982-16987出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1004498107
关键词
Akt; light-chain 3; neuronal autophagy; phenoxazine
资金
- National Institutes of Health, National Institute of Neurological Disorders and Stroke [2R01 NS039746, 2R01 NS045191]
- National Institute on Aging [2P01 AG022074]
- Gladstone Institutes
- Taube-Koret Center for Huntington Disease Research
- Hereditary Disease Foundation
- National Institutes of Health-National Institute of General Medical Sciences University of California
- San Francisco Medical Scientist Training Program
- University of California
- San Francisco Hillblom Center for the Biology of Aging
- National Institutes of Health [C06 RR018928]
Autophagy is an intracellular turnover pathway. It has special relevance for neurodegenerative proteinopathies, such as Alzheimer disease, Parkinson disease, and Huntington disease (HD), which are characterized by the accumulation of misfolded proteins. Although induction of autophagy enhances clearance of misfolded protein and has therefore been suggested as a therapy for proteinopathies, neurons appear to be less responsive to classic autophagy inducers than nonneuronal cells. Searching for improved inducers of neuronal autophagy, we discovered an N(10)-substituted phenoxazine that, at proper doses, potently and safely up-regulated autophagy in neurons in an Akt- and mTOR-independent fashion. In a neuron model of HD, this compound was neuroprotective and decreased the accumulation of diffuse and aggregated misfolded protein. A structure/activity analysis with structurally similar compounds approved by the US Food and Drug Administration revealed a defined pharmacophore for inducing neuronal autophagy. This pharmacophore should prove useful in studying autophagy in neurons and in developing therapies for neurodegenerative proteinopathies.
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