Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity.

The Journal of Pharmacology and Experimental Therapeutics
Preeti PutchaPamela J McLean

Abstract

Aggregation of alpha-synuclein (alphasyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and dementia with Lewy bodies. Lewy bodies contain alphasyn and several heat shock proteins (Hsp), a family of molecular chaperones up-regulated by the cell under stress. We have previously shown that direct expression of Hsp70 and pharmacological up-regulation of Hsp70 by geldanamycin, an Hsp90 inhibitor, are protective against alphasyn-induced toxicity and prevent aggregation in culture. Here, we use a novel protein complementation assay to screen a series of small-molecule Hsp90 inhibitors for their ability to prevent alphasyn oligomerization and rescue toxicity. By use of this assay, we found that several compounds prevented alphasyn oligomerization as measured by decreased luciferase activity, led to a reduction in high-molecular-mass oligomeric alphasyn, and protected against alphasyn cytotoxicity. A lead compound, SNX-0723 (2-fluoro-6-[(3S)-tetrahydrofuran-3-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide) was determined to have an EC(50) for inhibition of alphasyn oligomerization of approximately 48 nM and was able to rescue alphasyn-induced toxicity. In vivo assessment of SNX-0723 showe...Continue Reading

References

Aug 28, 1997·Nature·M G SpillantiniM Goedert
Jan 22, 2001·The Journal of Biological Chemistry·V N UverskyA L Fink
Nov 8, 2002·Journal of Neurochemistry·Pamela J McLeanBradley T Hyman
Nov 1, 2003·Science·A B SingletonK Gwinn-Hardy
Feb 3, 2004·Annals of Neurology·Juan J ZarranzJusto G de Yebenes
Feb 14, 2004·Human Molecular Genetics·Leonard PetrucelliMike Hutton
Mar 27, 2004·The Journal of Biological Chemistry·Jochen KluckenPamela J McLean
Sep 11, 2004·Biochemical and Biophysical Research Communications·Pamela J McLeanBradley T Hyman
Nov 24, 2004·The Journal of Biological Chemistry·Pavan K AuluckNancy M Bonini
Jan 27, 2005·The Journal of Biological Chemistry·Matthew M DedmonChristopher M Dobson
Feb 25, 2005·Molecular Therapy : the Journal of the American Society of Gene Therapy·Bakhos A TannousXandra O Breakefield
May 4, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ramesh K RamanathanMerrill J Egorin
Jan 6, 2006·Journal of Medicinal Chemistry·Huazhong HeGabriela Chiosis
Mar 2, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Omar M A El-AgnafDavid Allsop
Nov 14, 2006·Nature Methods·Ingrid Remy, Stephen W Michnick
Dec 23, 2006·Annals of the New York Academy of Sciences·Masahiro WazaGen Sobue
Feb 6, 2007·Bioorganic & Medicinal Chemistry Letters·Sabah AnsarBrian S J Blagg
Jul 3, 2007·Nature Chemical Biology·Anna RodinaGabriela Chiosis
Aug 24, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Karin M DanzerMarcus Kostka
Jan 4, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sarat ChandarlapatyDavid B Solit
Apr 3, 2008·PloS One·Tiago Fleming OuteiroPamela J McLean
Apr 26, 2008·The Journal of Biological Chemistry·Julie E TetzlaffPamela J McLean
May 31, 2008·Bioorganic & Medicinal Chemistry Letters·Thomas E BartaSteven E Hall
Jul 23, 2008·Current Opinion in Pharmacology·Tony TaldoneGabriela Chiosis
Aug 22, 2008·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·J C MöllerW H Oertel

❮ Previous
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Citations

May 8, 2013·Trends in Molecular Medicine·Angélique DeleersnijderVeerle Baekelandt
Oct 16, 2013·Trends in Biochemical Sciences·Michael Y Sherman, Shu-Bing Qian
Dec 9, 2010·Human Molecular Genetics·Emma DeasNicholas W Wood
Sep 30, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Karin M DanzerPamela J McLean
Jul 26, 2012·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Hemi DimantPamela J McLean
Dec 15, 2010·Molecular Neurodegeneration·Peizhou JiangShu-Hui C Yen
Aug 28, 2012·Molecular Neurodegeneration·Karin M DanzerPamela J McLean
Nov 21, 2013·Acta Neuropathologica Communications·Hemi DimantPamela J McLean
Dec 10, 2013·Acta Neuropathologica Communications·Darius Ebrahimi-FakhariLara Wahlster
Oct 30, 2014·Molecular Neurodegeneration·Simon MoussaudPamela J McLean
Dec 12, 2012·Neurotoxicity Research·Mathew B WongDean L Pountney
Feb 3, 2016·Frontiers in Neuroscience·Marion DelenclosPamela J McLean
Jan 13, 2015·Alzheimer's Research & Therapy·Woojin Scott KimGlenda M Halliday
Dec 9, 2015·Molecular Neurodegeneration·Anika M HelferichKarin M Danzer
Mar 19, 2015·Expert Opinion on Therapeutic Targets·Simon MoussaudPamela J McLean
Nov 12, 2014·BioMed Research International·Panchanan MaitiSally Frautschy
Oct 9, 2014·Annual Review of Pharmacology and Toxicology·William B PrattAndrew P Lieberman
Nov 20, 2012·Neurochemistry International·J GoodwinD L Pountney
Aug 16, 2016·Cellular and Molecular Life Sciences : CMLS·Sandeep K Sharma, Smriti Priya
Sep 2, 2016·Biomolecules & Therapeutics·Kyu-Yeon Jun, Youngjoo Kwon
Sep 30, 2016·Brain : a Journal of Neurology·Wolfgang WrasidloEliezer Masliah
May 11, 2010·Antiviral Research·Darci R SmithJohn H Connor
Apr 5, 2017·The Journal of Biological Chemistry·Dhruva D DhavalePaul T Kotzbauer
Jan 11, 2014·Therapeutic Advances in Neurological Disorders·Daryl Rhys JonesPamela McLean
Sep 16, 2017·Parkinson's Disease·Erik L FriesenSuneil K Kalia
Dec 12, 2012·Annals of Neurology·Lorraine V KaliaAnthony E Lang
Nov 9, 2011·The Neurologist·Maria Trinidad HerreroGurutz Linazasoro
Feb 15, 2012·The Journal of Physiology·Janine B LeeZhen Yan
Mar 7, 2020·Biomolecules·Margaux TeilBenjamin Dehay
May 28, 2011·Journal of Cellular Physiology·Monica CattaneoIda Biunno
Dec 20, 2011·Journal of Cellular and Molecular Medicine·Kurt A Jellinger
Apr 22, 2017·Frontiers in Neuroscience·Aaron Ciechanover, Yong Tae Kwon
Oct 8, 2013·Molecular and Cellular Biochemistry·Subhankar Paul, Sailendra Mahanta

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Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

Alpha-Synuclein Aggregation

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

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