title: Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.
abstract: Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aβ42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Steele
authors.forename: S
authors.initials: S
authors.lastname: Ju
authors.forename: M L
authors.initials: ML
authors.lastname: Lachenmayer
authors.forename: J
authors.initials: J
authors.lastname: Liken
authors.forename: A
authors.initials: A
authors.lastname: Stock
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: L M
authors.initials: LM
authors.lastname: Delgado
authors.forename: I E
authors.initials: IE
authors.lastname: Alfaro
authors.forename: S
authors.initials: S
authors.lastname: Bernales
authors.forename: G
authors.initials: G
authors.lastname: Verdile
authors.forename: P
authors.initials: P
authors.lastname: Bharadwaj
authors.forename: V
authors.initials: V
authors.lastname: Gupta
authors.forename: R
authors.initials: R
authors.lastname: Barr
authors.forename: A
authors.initials: A
authors.lastname: Friss
authors.forename: G
authors.initials: G
authors.lastname: Dolios
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Ringe
authors.forename: A A
authors.initials: AA
authors.lastname: Protter
authors.forename: R N
authors.initials: RN
authors.lastname: Martins
authors.forename: M E
authors.initials: ME
authors.lastname: Ehrlich
authors.forename: Z
authors.initials: Z
authors.lastname: Yue
authors.forename: G A
authors.initials: GA
authors.lastname: Petsko
authors.forename: S
authors.initials: S
authors.lastname: Gandy
mesh_terms: D016229:Amyloid beta-Peptides; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments; D012441:Saccharomyces cerevisiae; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D007211:Indoles; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); C010119:latrepirdine