A Novel %26quot;Molecular Tweezer%26quot; Inhibitor of alpha-Synuclein Neurotoxicity in Vitro and in Vivo

作者：Prabhudesai Shubhangi; Sinha Sharmistha; Attar Aida; Kotagiri Aswani; Fitzmaurice Arthur G; Lakshmanan Ravi; Ivanova Magdalena I; Loo Joseph A; Klaerner Frank Gerrit; Schrader Thomas; Stahl Mark; Bitan Gal^*; Bronstein Jeff M

来源：Neurotherapeutics, 2012, 9(2): 464-476.

DOI：10.1007/s13311-012-0105-1

• Parkinson%26apos
• s disease
• zebrafish
• synucleinopathy
• amyloid
• neuroprotection

Aggregation of alpha-synuclein (alpha-syn) is implicated as being causative in the pathogenesis of Parkinson%26apos;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 %26quot;molecular tweezer%26quot; (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 alpha-syn. In vitro, CLR01 inhibited the assembly of alpha-syn into beta-sheet-rich fibrils and caused disaggregation of pre-formed fibrils, as determined by thioflavin T fluorescence and electron microscopy. alpha-Syn toxicity was studied in cell cultures and was completely mitigated by CLR01 when alpha-syn was expressed endogenously or added exogenously. To determine if CLR01 was also protective in vivo, we used a novel zebrafish model of alpha-syn toxicity (alpha-syn-ZF), which expresses human, wild-type alpha-syn in neurons. alpha-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 alpha-syn aggregation in neurons, and reduced alpha-syn-induced apoptosis. alpha-Syn expression was found to inhibit the ubiquitin proteasome system in alpha-syn-ZF neurons, resulting in further accumulation of alpha-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%26apos;s disease and other synucleinopathies.

• 出版日期2012-4