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Hutchinson-Gilford Progeria Syndrome: Challenges at Bench and Bedside

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Biochemistry and Cell Biology of Ageing: Part II Clinical Science

Part of the book series: Subcellular Biochemistry ((SCBI,volume 91))

Abstract

The structural nuclear proteins known as “lamins” (A-type and B-type) provide a scaffold for the compartmentalization of genome function that is important to maintain genome stability. Mutations in the LMNA gene -encoding for A-type lamins- are associated with over a dozen of degenerative disorders termed laminopathies, which include muscular dystrophies, lipodystrophies, neuropathies, and premature ageing diseases such as Hutchinson Gilford Progeria Syndrome (HGPS). This devastating disease is caused by the expression of a truncated lamin A protein named “progerin”. To date, there is no effective treatment for HGPS patients, who die in their teens from cardiovascular disease. At a cellular level, progerin expression impacts nuclear architecture, chromatin organization, response to mechanical stress, and DNA transactions such as transcription, replication and repair. However, the current view is that key mechanisms behind progerin toxicity still remain to be discovered. Here, we discuss new findings about pathological mechanisms in HGPS, especially the contribution of replication stress to cellular decline, and therapeutic strategies to ameliorate progerin toxicity. In particular, we present evidence for retinoids and calcitriol (hormonal vitamin D metabolite) being among the most potent compounds to ameliorate HGPS cellular phenotypes in vitro, providing the rationale for testing these compounds in preclinical models of the disease in the near term, and in patients in the future.

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Authors and Affiliations

  1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Doisy Research Center, St Louis University School of Medicine, St. Louis, MO, USA

    Ray Kreienkamp & Susana Gonzalo

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  1. Ray Kreienkamp
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  2. Susana Gonzalo
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Correspondence to Susana Gonzalo .

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Editors and Affiliations

  1. Institute of Zoology, University of Mainz, Mainz, Germany

    J. Robin Harris

  2. Newcastle University, Newcastle upon Tyne, UK

    Viktor I. Korolchuk

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Kreienkamp, R., Gonzalo, S. (2019). Hutchinson-Gilford Progeria Syndrome: Challenges at Bench and Bedside. In: Harris, J., Korolchuk, V. (eds) Biochemistry and Cell Biology of Ageing: Part II Clinical Science. Subcellular Biochemistry, vol 91. Springer, Singapore. https://doi.org/10.1007/978-981-13-3681-2_15

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