title: Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans.
abstract: Defining the mechanisms of action of the antipsychotic drug (APD), clozapine, is of great importance, as clozapine is more effective and has therapeutic benefits in a broader range of psychiatric disorders compared with other APDs. Its range of actions have not been fully characterized. Exposure to APDs early in development causes dose-dependent developmental delay and lethality in Caenorhabditis elegans. A previous genome-wide RNAi screen for suppressors of clozapine-induced developmental delay and lethality revealed 40 candidate genes, including sms-1, which encodes a sphingomyelin synthase. One sms-1 isoform is expressed in the C. elegans pharynx, and its transgene rescues the sms-1 mutant phenotype. We examined pharyngeal pumping and observed that clozapine-induced inhibition of pharyngeal pumping requires sms-1, a finding that may explain the role of the gene in mediating clozapine-induced developmental delay/lethality. By analyzing multiple enzymes involved in sphingolipid metabolism, and by observing the effect of addition of various lipids directly to the worms, we suggest that glucosylceramide may be a key mediator of the effects of clozapine. We further observed that clozapine clears protein aggregates, such as α-synuclein, PolyQ protein, and α-1-antitrypsin mutant protein. In addition, it enhances ATG8/LC3. We conclude that clozapine appears to affect the development and induce lethality of worms, in part, through modulating glucosylceramide. We discuss the possible connections among glucosylceramide, protein aggregate clearance, and autophagy. Interactions, including mechanistic pathways involving these elements, may underlie some of the clinical effects of clozapine.
authors.affiliation: Program for Neuropsychiatric Research, Mailman Research Center 331, McLean Hospital, Belmont, MA, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Hao
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Oshrit
authors.initials: O
authors.lastname: Ben-David
authors.affiliation: Program for Neuropsychiatric Research, Mailman Research Center 331, McLean Hospital, Belmont, MA, USA.
authors.forename: Suzann M
authors.initials: SM
authors.lastname: Babb
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Program for Neuropsychiatric Research, Mailman Research Center 331, McLean Hospital, Belmont, MA, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Cohen
authors.affiliation: Program for Neuropsychiatric Research, Mailman Research Center 331, McLean Hospital, Belmont, MA, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Buttner
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000071190:Autophagy-Related Protein 8 Family / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D003024:Clozapine / Q000009:adverse effects / Q000494:pharmacology*; D005963:Glucosylceramides / Q000378:metabolism*; D007790:Lactosylceramides / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D000071190:Autophagy-Related Protein 8 Family; D029742:Caenorhabditis elegans Proteins; D005963:Glucosylceramides; D007790:Lactosylceramides; D066329:Protein Aggregates; C025575:lactotriaosylceramide; D003024:Clozapine