A Novel "Molecular Tweezer" Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

Shubhangi Prabhudesai, Sharmistha Sinha, Aida Attar, Aswani Kotagiri, Arthur G. Fitzmaurice, Ravi Lakshmanan, Magdalena I. Ivanova, Joseph A. Loo, Frank Gerrit Klärner, Thomas Schrader, Mark Stahl, Gal Bitan, Jeff M. Bronstein

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Summary: Aggregation of α-synuclein (α-syn) is implicated as being causative in the pathogenesis of Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Despite several therapies that improve symptoms in these disorders, none slow disease progression. Recently, a novel "molecular tweezer" (MT) termed CLR01 has been described as a potent inhibitor of assembly and toxicity of multiple amyloidogenic proteins. Here we investigated the ability of CLR01 to inhibit assembly and toxicity of α-syn. In vitro, CLR01 inhibited the assembly of α-syn into β-sheet-rich fibrils and caused disaggregation of pre-formed fibrils, as determined by thioflavin T fluorescence and electron microscopy. α-Syn toxicity was studied in cell cultures and was completely mitigated by CLR01 when α-syn was expressed endogenously or added exogenously. To determine if CLR01 was also protective in vivo, we used a novel zebrafish model of α-syn toxicity (α-syn-ZF), which expresses human, wild-type α-syn in neurons. α-Syn-ZF embryos developed severe deformities due to neuronal apoptosis and most of them died within 48 to 72 h. CLR01 added to the water significantly improved zebrafish phenotype and survival, suppressed α-syn aggregation in neurons, and reduced α-syn-induced apoptosis. α-Syn expression was found to inhibit the ubiquitin proteasome system in α-syn-ZF neurons, resulting in further accumulation of α-syn. Treatment with CLR01 almost completely mitigated the proteasome inhibition. The data suggest that CLR01 is a promising therapeutic agent for the treatment of Parkinson's disease and other synucleinopathies.

Original languageEnglish (US)
Pages (from-to)464-476
Number of pages13
JournalNeurotherapeutics
Volume9
Issue number2
DOIs
StatePublished - Apr 2012

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'A Novel "Molecular Tweezer" Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo'. Together they form a unique fingerprint.

  • Cite this

    Prabhudesai, S., Sinha, S., Attar, A., Kotagiri, A., Fitzmaurice, A. G., Lakshmanan, R., Ivanova, M. I., Loo, J. A., Klärner, F. G., Schrader, T., Stahl, M., Bitan, G., & Bronstein, J. M. (2012). A Novel "Molecular Tweezer" Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo. Neurotherapeutics, 9(2), 464-476. https://doi.org/10.1007/s13311-012-0105-1