A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model.
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.
Tsvetkov
Andrey S
AS
Gladstone Institute of Neurological Disease and Taube-Koret Center for Huntington's Disease Research and Consortium for Fronto-temporal Dementia Research, University of California, San Francisco, CA 94158, USA.
Miller
Jason
J
Arrasate
Montserrat
M
Wong
Jinny S
JS
Pleiss
Michael A
MA
Finkbeiner
Steven
S
D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D019610:Cytoprotection; D017277:Drug Approval; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases
C553100:10-(4'-(N-diethylamino)butyl)-2-chlorophenoxazine; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D010078:Oxazines; C039203:phenoxazine; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases