title: Yeast reveal a "druggable" Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons.
abstract: α-Synuclein (α-syn) is a small lipid-binding protein implicated in several neurodegenerative diseases, including Parkinson's disease, whose pathobiology is conserved from yeast to man. There are no therapies targeting these underlying cellular pathologies, or indeed those of any major neurodegenerative disease. Using unbiased phenotypic screens as an alternative to target-based approaches, we discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from α-syn toxicity. Three chemical genetic screens in wild-type yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5/Nedd4. These same steps were perturbed by α-syn itself. Thus, NAB identifies a druggable node in the biology of α-syn that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi vesicle trafficking.
authors.affiliation: Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Tardiff
authors.forename: Nathan T
authors.initials: NT
authors.lastname: Jui
authors.forename: Vikram
authors.initials: V
authors.lastname: Khurana
authors.forename: Mitali A
authors.initials: MA
authors.lastname: Tambe
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Thompson
authors.forename: Chee Yeun
authors.initials: CY
authors.lastname: Chung
authors.forename: Hari B
authors.initials: HB
authors.lastname: Kamadurai
authors.forename: Hyoung Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Alex K
authors.initials: AK
authors.lastname: Lancaster
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Buchwald
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D019610:Cytoprotection; D004353:Drug Evaluation, Preclinical; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D000075702:Nedd4 Ubiquitin Protein Ligases; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D056827:Endosomal Sorting Complexes Required for Transport; D018696:Neuroprotective Agents; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D051844:alpha-Synuclein; D043743:Ubiquitin-Protein Ligase Complexes; C000618479:NEDD4L protein, rat; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618484:Nedd4 protein, rat; D044767:Ubiquitin-Protein Ligases; C469287:RSP5 protein, S cerevisiae