Abstract
BackgroundSpinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. In SCA17, polyQ expansion occurs in the TATA box binding protein (TBP) and leads to the misfolding of TBP and the preferential degeneration in the cerebellar Purkinje neurons. Currently there is no effective treatment for SCA17. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a recently identified neurotrophic factor, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model, indicating that MANF could be a therapeutic target for treating SCA17.MethodsIn this study, we screened a collection of 2000 FDA-approved chemicals using a stable cell line expressing luciferase reporter, which is driven by MANF promoter. We identified several potential candidates that can induce the expression of MANF. Of these inducers, piperine is an agent that potently induces the luciferase expression or MANF expression.ResultsAddition of piperine in both cellular and mouse models of SCA17 alleviated toxicity caused by mutant TBP. Although mutant TBP is primarily localized in the nuclei, the polyQ expansion in TBP is able to induce ER stress, suggesting that nuclear misfolded proteins can also elicit ER stress as cytoplasmic misfolded proteins do. Moreover, piperine plays its protective role by reducing toxicity caused by the ER stress.ConclusionOur study established piperine as a MANF-based therapeutic agent for ER stress-related neuropathology in SCA17.
Highlights
Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine expansion
By crossing Mesencephalic astrocyte-derived neurotrophic factor (MANF) transgenic mice with TBP105Q KI mice, we found that MANF overexpression alleviated motor impairments in TATA box binding protein (TBP)-105Q KI mice [23]
Mutant TBP toxicity led to premature lethality in TBP-105Q KI mice, as death could be observed as early as 18 weeks, and more than 70% of mice died within 30 weeks
Summary
Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a recently identified neurotrophic factor, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model, indicating that MANF could be a therapeutic target for treating SCA17. In SCA17, the polyQ expansion occurs in the TATA box-binding protein (TBP) [3], a well-known general transcription factor that plays important roles in mediating transcription by all three nuclear RNA polymerases [4, 5]. Neurotrophic factors, such as BDNF, play important roles in mediating neuronal development, functions, and survival [17], and have long been studied as potential. We identified MANF as a target downregulated by TBP with polyQ expansion, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model [23], indicating that MANF is a potential therapeutic target for SCA17 treatment
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