Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain
John W. Steele,Shulin Ju,M.L. Lachenmayer,M.L. Lachenmayer,J. Liken,Aryeh Stock,Soong Ho Kim,Luz Delgado,Iván E. Alfaro,Sebastian Bernales,Giuseppe Verdile,Prashant Bharadwaj,Veer Bala Gupta,Renae Barr,A. Friss,Georgia Dolios,Rong Wang,Dagmar Ringe,Andrew Asher Protter,Ralph N. Martins,Ralph N. Martins,Ralph N. Martins,Michelle E. Ehrlich,Zhenyu Yue,Gregory A. Petsko,Gregory A. Petsko,Sam Gandy,Sam Gandy +27 more
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TLDR
It is proposed 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.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.read more
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References
More filters
Journal ArticleDOI
Huntington's disease.
TL;DR: Effective intervention by clinicians is possible in terms of providing patients and families with accurate information about the disease, counseling them about availability of genetic testing at specialized centers, and in giving them sound advice regarding work, driving, relationships, finances, research participation, and support groups.
Journal ArticleDOI
α-Synuclein Blocks ER-Golgi Traffic and Rab1 Rescues Neuron Loss in Parkinson's Models
Antony A. Cooper,Aaron D. Gitler,Anil G. Cashikar,Cole M. Haynes,Kathryn J. Hill,Bhupinder Bhullar,Bhupinder Bhullar,Kangning Liu,Kangning Liu,Kexiang Xu,Katharine E. Strathearn,Fang Liu,Songsong Cao,Kim A. Caldwell,Guy A. Caldwell,Gerald T. Marsischky,Richard D. Kolodner,Joshua LaBaer,Jean-Christophe Rochet,Nancy M. Bonini,Nancy M. Bonini,Susan Lindquist +21 more
TL;DR: Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-induced dopaminergic neuron loss in animal models of PD, suggesting synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.
Journal ArticleDOI
Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in Yeast
Takeshi Noda,Yoshinori Ohsumi +1 more
TL;DR: It is found that Tor, a phosphatidylinositol kinase homologue, is involved in the control of autophagy in the yeast, Saccharomyces cerevisiae, and that a high concentration of cAMP is inhibitory for induction of Autophagy.
Journal ArticleDOI
α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation
TL;DR: It is proposed that destabilization of the helically folded tetramer precedes α-synuclein misfolding and aggregation in Parkinson’s disease and other human synucleinopathies, and that small molecules that stabilize the physiological tetramer could reduce α- Synuclein pathogenicity.
Journal ArticleDOI
Yeast Cells Provide Insight into Alpha-Synuclein Biology and Pathobiology
Tiago F. Outeiro,Susan Lindquist +1 more
TL;DR: This readily manipulable system provides an opportunity to dissect the molecular pathways underlying normal alpha-synuclein biology and the pathogenic consequences of its misfolding.