Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models

Abstract

In spinocerebellar ataxia type 17 (SCA17), the expansion of a translated CAG repeat in the TATA box binding protein (TBP) gene results in a long polyglutamine (polyQ) tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q₇₉-green fluorescent protein (GFP) expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q₇₉ cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment.

Keywords:

• spinocerebellar ataxia type 17
• TATA box binding protein
• polyQ aggregation
• indole and derivative
• therapeutics

Acknowledgments

We thank the Molecular Imaging Core Facility of National Taiwan Normal University for the technical assistance. This work was supported by grants MOST103-2325-B-003-001 and MOST103-2325-B-003-003 from the Ministry of Science and Technology and grants 103T3040B05 and 103T3040B07 from National Taiwan Normal University, Taipei, Taiwan.

Disclosure

The authors report no conflicts of interest in this work.