A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model
1. Andrey S. Tsvetkov a,
2. Jason Miller a,b,c,
3. Montserrat Arrasate a,
4. Jinny S. Wong a,
5. Michael A. Pleiss a, and
6. Steven Finkbeiner a,d,e,f,g,1
Author Affiliations
a Gladstone Institute of Neurological Disease and the Taube–Koret Center for Huntington's Disease Research and the Consortium for Fronto-temporal Dementia Research, University of California, San Francisco, CA 94158; and
b Chemistry and Chemical Biology Program,
c Medical Scientist Training Program,
d Neuroscience Program,
e Biomedical Sciences Program, and
Departments of f Neurology and
g Physiology, University of California, San Francisco, CA 94143
Abstract
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 N10-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. |
