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Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease

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Abstract

Tay-Sachs disease (TSD) is a lethal lysosomal storage disease (LSD) caused by mutations in the HexA gene, which can lead to deficiency of β-hexosaminidase A (HexA) activity and consequent accumulation of its substrate, GM2 ganglioside. Recent reports that progranulin (PGRN) functions as a chaperone of lysosomal enzymes and its deficiency is associated with LSDs, including Gaucher disease and neuronal ceroid lipofuscinosis, prompted us to screen the effects of recombinant PGRN on lysosomal storage in fibroblasts from 11 patients affected by various LSDs, which led to the isolation of TSD in which PGRN demonstrated the best effects in reducing lysosomal storage. Subsequent in vivo studies revealed significant GM2 accumulation and the existence of typical TSD cells containing zebra bodies in both aged and ovalbumin-challenged adult PGRN-deficient mice. In addition, HexA, but not HexB, was aggregated in PGRN-deficient cells. Furthermore, recombinant PGRN significantly reduced GM2 accumulation and lysosomal storage in these animal models. Mechanistic studies indicated that PGRN bound to HexA through granulins G and E domain and increased the enzymatic activity and lysosomal delivery of HexA. More importantly, Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively bound to HexA and reduced the GM2 accumulation. Collectively, these studies not only provide new insights into the pathogenesis of TSD but may also have implications for developing PGRN-based therapy for this life-threatening disorder.

Key messages

  • GM2 accumulation and the existence of typical TSD cells containing zebra bodies are detected in both aged and ovalbumin-challenged adult PGRN deficient mice.

  • Recombinant PGRN significantly reduces GM2 accumulation and lysosomal storage both in vivo and in vitro, which works through increasing the expression and lysosomal delivery of HexA.

  • Pcgin, an engineered PGRN derivative bearing the granulin E domain, also effectively binds to to HexA and reduces GM2 accumulation.

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Funding

This work was supported partly by NIH research grants 1R01NS103931, R01AR062207, and R01AR061484 and a DOD research grant W81XWH-16-1-0482. Yuehong Chen was funded by China Scholarship Council (grant number 201606240021).

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  1. Yuehong Chen and Jinlong Jian contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopaedic Surgery, New York University Medical Center, 301 East 17th Street, New York, NY, 10003, USA

    Yuehong Chen, Jinlong Jian, Aubryanna Hettinghouse & Chuan-ju Liu

  2. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Yuehong Chen

  3. The Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 45229, USA

    Xueheng Zhao, Kenneth D. R. Setchell & Ying Sun

  4. Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA

    Chuan-ju Liu

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  1. Yuehong Chen
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Correspondence to Chuan-ju Liu.

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Chen, Y., Jian, J., Hettinghouse, A. et al. Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease. J Mol Med 96, 1359–1373 (2018). https://doi.org/10.1007/s00109-018-1703-0

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