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Trehalose Attenuates the Gait Ataxia and Gliosis of Spinocerebellar Ataxia Type 17 Mice

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Abstract

Spinocerebellar ataxia type 17 (SCA17) is caused by CAG/CAA repeat expansion on the gene encoding a general transcription factor, TATA-box-binding protein (TBP). The CAG repeat expansion leads to the reduced solubility of polyglutamine TBP and induces aggregate formation. The TBP aggregation, mostly present in the cell nuclei, is distinct from that in most other neurodegenerative diseases, in which the aggregation is formed in cytosol or extracellular compartments. Trehalose is a disaccharide issued by the Food and Drug Administration with a Generally Recognized As Safe status. Lines of evidence suggest trehalose could prevent protein aggregate formation in several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In this study, we evaluated the therapeutic potential of trehalose on SCA17 using cerebellar primary and organotypic culture systems and a mouse model. Our results showed that TBP nuclear aggregation was significantly decreased in both the primary and slice cultures. Trehalose (4 %) was further supplied in the drinking water of SCA17 transgenic mice. We found both the gait behavior in the footprint analysis and motor coordination in the rotarod task were significantly improved in the trehalose-treated SCA17 mice. The cerebellar weight was increased and the astrocyte gliosis was reduced in SCA17 mice after trehalose treatment. These data suggest that trehalose could be a potential nontoxic treatment for SCA17.

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Abbreviations

AD:

Alzheimer’s disease

ANOVA:

Analysis of variance

DIV:

Days in vitro

DRPLA:

Dentatorubral–pallidoluysian atrophy

FDA:

Food and Drug Administration

GFAP:

Glial fibrillary acidic protein

GRAS:

Generally Recognized As Safe

HD:

Huntington’s disease

LSD:

Least significant difference

PD:

Parkinson’s disease

polyQ:

Polyglutamine

SBMA:

Spinal and bulbar muscular atrophy

SCA:

Spinocerebellar ataxias

SCA17:

Spinocerebellar ataxia type 17

TBP:

TATA-box-binding protein

TBS:

Tris buffered saline

TG:

Transgenic

WT:

Wild-type

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Acknowledgments

We thank Wei-Lin Chen and Wei-I Chen for their technical help. This work was supported in part by research Grants from the National Science Council (NSC 100-2325-B-003-002, NSC 101-2325-B-003-001, NSC 102-2325-B-003-001, and MOST 103-2325-B-003-003), and National Taiwan Normal University (103T3040B07). Our gratitude is extended to the Molecular Imaging Core Facility of National Taiwan Normal University under the auspices of the Ministry of Science and Technology.

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Authors and Affiliations

  1. Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

    Zhi-Zhong Chen, Chien-Ming Wang, Guan-Chiun Lee, Ho-Chiang Hsu, Tzu-Ling Wu, Chia-Wei Lin, Chih-Kang Ma, Guey-Jen Lee-Chen & Hsiu Mei Hsieh-Li

  2. Department of Nursing, Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan

    Hei-Jen Huang

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  1. Zhi-Zhong Chen
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Electronic supplementary material

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11064_2015_1530_MOESM1_ESM.pdf

Supplementary material Fig. 1S. Characterization of neurite outgrowth and aggregation of Purkinje neurons in mouse cerebellar primary culture. (A) Immunofluorescent staining of the Purkinje neurons by IP3R1 antibody after culture for different periods. Scale bar = 40 μM. (B) The neurite outgrowth of Purkinje neurons was reduced in the SCA17 mouse primary culture compared to the wild-type group. ***, p < 0.001. (C) The TBP aggregations in the Purkinje cells of SCA17 mice were significantly increased at DIV14 and 21 compared to wild-type mice. *, p < 0.05; ***, p < 0.001. (120-200 Purkinje cells were analyzed per mouse; n = 3) (PDF 315 kb)

11064_2015_1530_MOESM2_ESM.pdf

Supplementary material Fig. 2S. Establishment of mouse cerebellar organotypic slice culture. (A) Immunofluorescent staining analysis of the TBP aggregation (identified by 1TBP18 antibody) in SCA17 mouse cerebellar Purkinje neurons (identified by IP3R1 antibody). No significant TBP aggregation was identified in either the wild-type or SCA17 transgenic mouse cerebella at postnatal day 7 (p7) and 14 (p14). Only a higher TBP signal was detected in the Purkinje neuron nuclei at p14. Scale bar = 150 μm (top panels) and 40 μm (bottom panels). (B) The cerebellar slices from p7 mice were cultured for 7 days in vitro (DIV7). The cerebellar slices were kept in normal morphology during the culture period. The TBP aggregation in Purkinje neurons was identified by immunofluorescent staining with 1TBP18 antibody. The TBP aggregation was shown at DIV3. It was significant at DIV7 in transgenic mouse Purkinje cell nuclei, and no aggregation was identified in the wild-type slice. Scale bar = 40 μm (a, d), 8 μm (b, e), 4 μm (c), 10 μm (f). (4-6 slices per mouse; n = 4) (PDF 540 kb)

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Chen, ZZ., Wang, CM., Lee, GC. et al. Trehalose Attenuates the Gait Ataxia and Gliosis of Spinocerebellar Ataxia Type 17 Mice. Neurochem Res 40, 800–810 (2015). https://doi.org/10.1007/s11064-015-1530-4

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