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Altered glucose metabolism and its association with carbonic anhydrase 8 in Machado-Joseph Disease

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Abstract

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disease. This disorder is caused by polyglutamine (polyQ)-containing mutant ataxin-3, which tends to misfold and aggregate in neuron cells. We previously demonstrated a protective function of carbonic anhydrase 8 (CA8) in MJD disease models and a decreased glycolytic activity associated with down-regulated CA8 in a human osteosarcoma (OS) cell model. Given that a reduction in body weight accompanied by gait and balance instability was observed in MJD patients and transgenic (Tg) mice, in this study, we aimed to examine whether metabolic defects are associated with MJD and whether CA8 expression is involved in metabolic dysfunction in MJD. Our data first showed that glucose uptake ability decreases in cells harboring mutant ataxin-3, but increases in cells overexpressing CA8. In addition, the expressions of glucose transporter 3 (GLUT3) and phosphofructokinase-1 (PFK1) were significantly decreased in the presence of mutant ataxin-3. Consistently, immunohistochemistry (IHC) showed that GLUT3 was less expressed in cerebella of aged MJD Tg mice, indicating that the dysfunction of GLUT3 may be associated with late-stage disease. On the other hand, transient down-regulation of CA8 revealed decreased expressions of GLUT3 and PFK1 in HEK293 cells harboring wild-type (WT) ataxin-3, but no further reduction of GLUT3 and PFK1 expressions were observed in HEK293 cells harboring mutant ataxin-3. Moreover, immunoprecipitation (IP) and immunofluorescence (IF) demonstrated that interactions exist between ataxin-3, CA8 and GLUT3 in MJD cellular and Tg models. These lines of evidence suggest that CA8 plays an important role in glucose metabolism and has different impacts on cells with or without mutant ataxin-3. Interestingly, the decreased relative abundance of Firmicutes/Bacteroidetes (F/B) ratio in the feces of aged MJD Tg mice coincided with weight loss and metabolic dysfunction in MJD. Taken together, our results are the first to demonstrate the effects of CA8 on glucose metabolism and its involvement in the metabolic defects in MJD disease. Further investigations will be required to clarify the underlying mechanisms for the metabolic defects associated with MJD.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ATP:

Adenosine triphosphate

Bax:

Bcl-2-associated X

BMI:

Body Mass Index

CO2:

Carbon dioxide

CA8:

Carbonic anhydrase 8

CGNs:

Cerebellar granule neurons

DUB:

Deubiquitinating enzyme

DNA:

Deoxyribonucleic acid

ERAD:

Endoplasmic reticulum-associated degradation

EGFP:

Enhanced green fluorescent protein

F6P:

Fructose-6-phosphate

F1,6BP:

Fructose-1,6-bisphosphate

FBS:

Fetal bovine serum

F/B:

Firmicutes/Bacteroidetes

GLUT3:

Glucose transporter 3

GST:

Glutathione S-transferase

GAPDH:

Glyceraldehyde-3-phosphate-dehydrogenase

HRP:

Horseradish peroxidase

HD:

Huntington’s disease

IHC:

Immunohistochemistry

IP:

Immunoprecipitation

IF:

Immunofluorescence

IP3:

Inositol 1,4,5-trisphosphate

IP3R1:

Inositol 1,4,5 trisphosphate receptor type 1

MJD:

Machado–Joseph disease

MEM:

Minimum Essential Medium

2-NBDG:

2-[N-(7-nitrobenz-2-oxa1,3-diazol-4-yl)-amino]-2-deoxyglucose

NGS:

Normal goat serum

N.S.:

Non-significant

OS:

Osteosarcoma

PA:

Paraformaldehyde

PBS:

Phosphate buffered saline

PFK1:

Phosphofructokinase-1

polyQ:

Polyglutamine

PET:

Positron Emission Tomography

ROS:

Reactive oxygen species

shRNA:

Short hairpin RNA

SDS:

Sodium dodecyl sulfate

SCA3:

Spinocerebellar ataxia type 3

STS:

Staurosporine

TBP:

TATA-binding protein

Tg:

Transgenic

wdl:

Waddles

WT:

Wild-type

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Acknowledgements

We thank the National RNAi Core Facility at Academia Sinica in Taiwan for providing the RNAi reagents and related services; Drs. Shin‐Lan Hsu and Hsi‐Chi Lu for providing the cell lines; Drs. Henry Paulson and Toshikazu Suzuki for providing plasmids; Yu-Hsin Lin, Yi-Hua Tsai, and Yi-Ling Chiu for technical support.

Funding

This work was supported by grants from the Ministry of Science and Technology of the Republic of China (MOST105-2632-B-029-001; MOST105-2320-B-029-001-MY3; MOST109-2320-B-029-001).

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Author notes

  1. Guan-Yu Lin and Chung-Yung Ma contributed equally to this work.

Authors and Affiliations

  1. Department of Life Science, Tunghai University, No.1727, Sec. 4, Taiwan Boulevard, Taichung, 407, Taiwan, Republic of China

    Guan-Yu Lin, Chung-Yung Ma, Li-Chung Kuo, Hanbing Wang & Mingli Hsieh

  2. Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China

    Benjamin Y. Hsieh

  3. Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan, Republic of China

    Chin-San Liu

  4. Life Science Research Center, Tunghai University, Taichung, Taiwan, Republic of China

    Mingli Hsieh

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Contributions

MH, GYL and CYM conceived and designed the study; GYL, CYM, LCK and HW performed the experiments; CYM, LCK, BYH and HW analyzed data; CYM and BYH provided statistical analysis; CSL and MH provided research resources; GYL, CYM, LCK, BYH, CSL and MH wrote and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Mingli Hsieh.

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Lin, GY., Ma, CY., Kuo, LC. et al. Altered glucose metabolism and its association with carbonic anhydrase 8 in Machado-Joseph Disease. Metab Brain Dis 37, 2103–2120 (2022). https://doi.org/10.1007/s11011-022-00994-7

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