Details

Autor(en) / Beteiligte

• Tsvetkov, Andrey S
• Miller, Jason
• Arrasate, Montserrat
• Wong, Jinny S
• Pleiss, Michael A
• Finkbeiner, Steven

Titel

small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2010-09, Vol.107 (39), p.16982-16987

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.