No abstract

The protein mutated in Huntington's disease is phosphorylated by the inflammatory kinase IKK, which promotes other post-translational modifications, and protein degradation.

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.Akt | light-chain 3 | neuronal autophagy | phenoxazine M acroautophagy (hereafter referred to as autophagy) is used by cells to remove long-lived proteins, organelles, or parasites (1) and involves sequestration of material inside doublemembrane vesicles called autophagosomes, which fuse to lysosomes to degrade vesicle contents for reuse in cellular processes. Autophagy is important in neuronal survival: Mice deficient in autophagy develop neurodegeneration (2). Deficient autophagy might allow accumulation of misfolded proteins that lead to neurodegenerative proteinopathies (3). In cell lines, clearance of mutated α-synuclein, implicated in Parkinson disease, depends on autophagy (4). Other examples of autophagy's involvement in neurodegeneration are amyotrophic lateral sclerosis (5), Huntington disease (HD) (6), and Alzheimer disease (7).Studies in cell lines and fly models of neurodegenerative diseases suggest that autophagy can be enhanced to remove misfolded proteins and might be therapeutical (1). One of the best-studied pharmacological inducers of autophagy is rapamycin, which inhibits mTOR, a key regulator of cell growth and proliferation. In cell line and fly models, rapamycin slows accumulation of misfolded proteins implicated in several neurodegenerative diseases (1). In a mouse model of HD, everolimus, a rapamycin analogue, induced autophagy in muscle but not in brain (8). Compounds that decrease inositol levels also induce autophagy (5, 9). Screens for small-molecule enhancers of autophagy in nonneuronal cells yielded a diverse set of structurally unrelated autophagy activators, some of which might act via similar pathways (9-11).Autophagy stimulators have been studied mainly in nonneuronal cells and cell lines. However, autophagy might be regulated differently in primary neurons and other cell types (12). Chemical inhibition of the proteasome affects lipidated ligh...