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.

Neuroprotection of Indole-Derivative Compound NC001-8 by the Regulation of the NRF2 Pathway in Parkinson’s Disease Cell Models

“…As an indole-derivative compound with an aromatic structure (Figure 1(a)), NC001-8, at a concentration of 100 nM, has demonstrated its neuroprotective potential in SCA cell models [22, 23]. Before examining the neuroprotective potential of NC001-8 in PD, we first evaluated its neurotoxicity in DAergic neurons.…”

“…The differentiation of DAergic neurons was induced by incubation with 120 nM of TPA (Sigma-Aldrich) for 14 days. Cells were treated with MPP + (1 mM, Sigma-Aldrich) and/or indole derivative NC001-8 (0.1 μ M) [22, 23] for 2 days and/or 14 days, respectively.…”

“…Another endogenous indole derivative, indolepropionamide, was also shown to prolong rotifer lifespan and recover the mitochondrial metabolic function in rodents by decreasing the generation of free radicals [21]. We have previously demonstrated that the indole derivative NC001-8 is able to mitigate oxidative stress and polyglutamine (polyQ) aggregation by upregulated chaperones and/or autophagy in spinocerebellar ataxia-type (SCA) cell models [22, 23]. In the present study, we examined the effect of NC001-8 in MPP + -treated DAergic neurons derived from SH-SY5Y cells, focusing particularly on the maintenance of neuronal survival and reduction of ROS by increasing NRF2 and NQO1 expression.…”

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

“…Treatment with GGA decreased mutant protein aggregation in SCA3 and SCA17 cells [205,210], but had no effect on mutant ataxin-3 toxicity in SCA3 Drosophila [141]. Indole and its derivate NC001-8 were recently tested in SCA models.…”

“…Indole and its derivate NC001-8 were recently tested in SCA models. Although the mechanisms by which these compounds induce chaperone expression remain uncertain, both decreased mutant protein aggregation in SCA3 and SCA17 cells [205,210], being reported to enhance autophagy in SCA3 cells [205].…”