Abstract
Spinocerebellar ataxia (SCA) type 17 is an autosomal dominant ataxia caused by expanded polyglutamine (polyQ) tract in the TATA-box binding protein (TBP). Substantial studies have shown involvement of compromised mitochondria biogenesis regulator peroxisome proliferator-activated receptor gamma-coactivator 1 alpha (PGC-1α), nuclear factor erythroid 2-related factor 2 (NRF2), nuclear factor-Y subunit A (NFYA), and their downstream target genes in the pathogenesis of polyQ-expansion diseases. The extracts of Paeonia lactiflora (P. lactiflora) and Glycyrrhiza uralensis (G. uralensis) have long been used as a Chinese herbal medicine (CHM). Shaoyao Gancao Tang (SG-Tang) is a formulated CHM made of P. lactiflora and G. uralensis at a 1:1 ratio. In the present study, we demonstrated the aggregate-inhibitory and anti-oxidative effect of SG-Tang in 293 TBP/Q79 cells. We then showed that SG-Tang reduced the aggregates and ameliorated the neurite outgrowth deficits in TBP/Q79 SH-SY5Y cells. SG-Tang upregulated expression levels of NFYA, PGC-1α, NRF2, and their downstream target genes in TBP/Q79 SH-SY5Y cells. Knock down of NFYA, PGC-1α, and NRF2 attenuated the neurite outgrowth promoting effect of SG-Tang on TBP/Q79 SH-SY5Y cells. Furthermore, SG-Tang inhibited aggregation and rescued motor-deficits in SCA17 mouse model. The study results suggest the potential of SG-Tang in treating SCA17 and probable other polyQ diseases.
Highlights
A group of inherited neurodegenerative diseases including Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA), hereditary spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7 and 17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by an expansion of unstable trinucleotide (CAG) repeats encoding expanded polyglutaminetracts [1]
Studies have shown PGC-1α/SOD2/CYCS and nuclear factor erythroid 2-related factor 2 (NRF2)/glutamate-cysteine ligase catalytic subunit (GCLC)/NQO1 pathways are involved in pathogenesis of polyQ-mediated diseases including HD and SCA3 [18, 20, 23, 24], and impaired nuclear factor-Y subunit A (NFYA)/HSPA5 expression has been shown in SCA17, including cellular and animal models and lymphoblasts from patients [6, 7, 9]
PGC-1α/SOD2/CYCS, NRF2/GCLC/NQO1, and NFYA/HSPA5 pathways may serve as the therapeutic targets for SCAs
Summary
A group of inherited neurodegenerative diseases including Huntington’s disease (HD), spinobulbar muscular atrophy (SBMA), hereditary spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7 and 17, and dentatorubral-pallidoluysian atrophy (DRPLA) are caused by an expansion of unstable trinucleotide (CAG) repeats encoding expanded polyglutamine (polyQ)tracts [1]. SCA17 is an autosomal dominant ataxia caused by an allele containing expanded repeats longer than 43 in the TATA-box binding protein (TBP) gene, a transcription initiation factor [2]. The presence of expanded polyQ proteins leads to transcriptional dysregulation, mitochondrial damage, oxidative stress, defect in axonal transport, chaperone-proteasome impairment, autophagolysosome dysfunction, and unfolded protein response (UPR) in endoplasmic reticulum (ER) [3, 4]. We and Huang et al have shown that TBP-containing expanded polyQ interacted aberrantly with nuclear factor-Y (NFY) subunit A (NFYA), which would result in reduced heat shock 70 kDa protein 5 (HSPA5) expression [6, 7], a major ER chaperone and master regulator of UPR [8]. NFY-HSPA5 may serve as a potential target for development of therapeutics for SCA17
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