Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.

TitleLatrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.
Publication TypeJournal Article
Year of Publication2013
AuthorsSteele JW, Ju S, Lachenmayer ML, Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S
JournalMol Psychiatry
Volume18
Issue8
Pagination882-8
Date Published2013 Aug
ISSN1476-5578
Keywordsalpha-Synuclein, Amyloid beta-Peptides, Animals, Autophagy, Brain, Cell Death, Cells, Cultured, Humans, Indoles, Male, Mice, Neuroprotective Agents, Peptide Fragments, Saccharomyces cerevisiae
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.

DOI10.1038/mp.2012.115
Alternate JournalMol. Psychiatry
PubMed ID22869031
PubMed Central IDPMC3523214
Grant ListP01 AG010491 / AG / NIA NIH HHS / United States
P01AG10491 / AG / NIA NIH HHS / United States
P30 NS061777 / NS / NINDS NIH HHS / United States
P30 NS061777 / NS / NINDS NIH HHS / United States
P50AG05138 / AG / NIA NIH HHS / United States
R01 NS075685 / NS / NINDS NIH HHS / United States
R01NS060123 / NS / NINDS NIH HHS / United States
S10 RR022415 / RR / NCRR NIH HHS / United States
T32 GM062754 / GM / NIGMS NIH HHS / United States
T32GM062754 / GM / NIGMS NIH HHS / United States
U54RR022220 / RR / NCRR NIH HHS / United States